BR112021008969A2 - compounds and compositions to treat conditions associated with nlrp activity - Google Patents

Abstract

the present invention relates to compounds of formula aa or a pharmaceutically acceptable salt thereof: formula aa or a pharmaceutically acceptable salt thereof, wherein the variables shown in formula a may be as defined elsewhere herein.

Description

Patent Descriptive Report for "COMPOUNDS AND COMPOSITIONS TO TREAT AFFECTS ASSOCIATED WITH NLRP ACTIVITY".

FIELD OF TECHNIQUE

[001] The present invention relates to chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal and/or drug combination of the compound) that are useful, for example, to treat a condition, disease, or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., a condition, disease, or disorder associated with - tion of NLRP3) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder in an individual (eg, a human). This disclosure also discloses compositions, as well as other methods of using and manufacturing the same.

[002] The present disclosure also relates, in part, to methods and compositions for treating anti-TNFα resistance in a subject with an NLRP3 antagonist. The present disclosure also pertains, in part, to methods, combinations and compositions for treating diseases related to TFNα and anti-TNFα resistance in a subject which include the administration of an NLRP3 antagonist, an NLRP3 antagonist and a anti-TNFα agent, or a composition comprising an NLRP3 antagonist and an anti-TNFα agent.

BACKGROUND

[003] The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited diseases such as cryopyrin-associated periodic syndromes (CAPS). Inherited CAPS Muckle-Wells syndrome (MWS), familial cold-related autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are examples of indications that have been reported to be associated with the gain of functional mutations in NLRP3.

[004] NLRP3 can form a complex and has been implicated in the pathogenesis of several complex diseases, including but not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, as well as diseases of the central nervous system. , such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson's disease, lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis, liver diseases such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic diseases, such as acute and chronic pancreatitis, kidney diseases, such as acute and chronic kidney injury, intestinal diseases, such as Crohn's disease and Ulcerative Colitis, skin disease, such as psoriasis, musculoskeletal disease, such as such as scleroderma, vessel disorder such as giant cell arteritis, bone disorders such as Osteoarthritis, osteoporosis and osteopetrosis disorders, eye diseases such as glauc oma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune diseases such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.

[005] In light of the above, it would be desirable to provide compounds that modulate (eg, antagonize) NLRP3.

[006] Several patients who have inflammatory or autoimmune diseases are treated with anti-TNFα agents. A subpopulation of such patients develop resistance to treatment with anti-TNFα agents. It is desirable to develop methods to reduce a patient's resistance to anti-TNFα agents. In light of this, it would also be desirable to provide alternative therapies to treat inflammatory or autoimmune diseases (e.g. NLRP3 inflammasome inhibitors) to prevent

tar or minimize the use of anti-TNFα agents.

[007] Inflammatory bowel diseases (IBD), encompassing Ulcerative Colitis (UC) and Crohn's disease (CD), are chronic diseases characterized by barrier dysfunction and uncontrolled inflammation and mucosal immune reactions in the gastrointestinal tract. Several inflammatory pathways have been implicated in the progression of IBD, and anti-inflammatory therapy such as tumor necrosis factor alpha (TNF-α) blockade has shown clinical efficacy (Rutgeerts P et al N Engl J Med 2005; 353 :2462 to 2476). Anti-TNFα therapies, however, do not show complete efficacy, however, other cytokines, such as IL-1β, IL-6, IL-12, IL-18, IL-21 and IL-23, have been shown to trigger the pathology of inflammatory disease in IBD (Neurath MF Nat Rev Immunol 2014;14;329 to 342). IL-1β and IL-18 are produced by the NLRP3 inflammasome in response to pathogenic danger signals and have been shown to play a role in IBD. Anti-IL-1β therapy is effective in patients with IBD triggered by genetic mutations in CARD8 or IL-10R (Mao L et al, J Clin Invest 2018;238:1793 to 1806, Shouval DS et al, Gastroenterology 2016;151:1100 to 1104), IL-18 genetic polymorphisms have been linked to UC (Kanai T et al, Curr Drug Targets 2013;14:1392 to 1399), and NLRP3 inflammasome inhibitors have been shown to be effective in modern IBD mice (Perera AP et al, Sci Rep 2018;8:8618). Resident gastrointestinal tract immune cells isolated from the lamina propria of IBD patients can produce IL-1β, either spontaneously or when stimulated by LPS, and this production of IL-1β can be blocked by the ex vivo addition of an NLRP3 antagonist. Based on strong clinical and preclinical evidence showing that IL-1β and inflammasome-triggered IL-18 play a role in IBD pathology, it is clear that NLRP3 inflammasome inhibitors could be an effective treatment option for UC, Crohn's disease. or subsets of patients with IBD. These subsets of patients could be defined by their peripheral and gastrointestinal tract levels of inflammasome-related cytokines, including IL-1β, IL-6, and IL-18, by genetic factors that predispose patients with IBD to have IBD activation. NLRP3 inflammasome, such as mutations in genes including ATG16L1, CARD8, IL-10R or PTPN2 (Saitoh T et al, Nature 2008;456:264, Spalinger MR, Cell Rep 2018;22:1835) or for other clinical grounds, such as as non-response to TNF therapy.

[008] Although anti-TNF therapy is an effective treatment option for Crohn's disease, 40% of patients fail to respond. One-third of unresponsive CD patients failed to respond to anti-TNF therapy at baseline, while another one-third lost response to treatment over time (secondary nonresponse). The secondary non-response may be due to the generation of anti-drug antibodies or a change in the immune compartment that desensitizes the patient to anti-TNF (Ben-Horin S et al, Autoimmun Rev 2014;13:24 to 30, Steenholdt C et al. Gut 2014;63:919 to 927). Anti-TNF reduces inflammation in IBD by causing pathogenic T cell apoptosis in the intestine, thereby eliminating the T cell-mediated inflammatory response (Van den Brande et al Gut 2007:56:509 to 517). There is increased NLRP3 expression and increased IL-1β production in the gastrointestinal tract of TNF-nonresponsive CD patients (Leal RF et al Gut 2015;64:233 to 242) compared to TNF-responsive patients, suggesting activation of TNF NLRP3 inflammatory trajectory. In addition, there is increased expression of TNF receptor 2 (TNF-R2), which allows for TNF-mediated proliferation of T cells (Schmitt H et al Gut 2018;0:1 to 15). IL-1β signaling in the gastrointestinal tract promotes the differentiation of T cells into Th1/17 cells, which can escape anti-TNF-α-mediated apoptosis. It is likely, therefore, that NLRP3 inflammasome activation may cause non-responsiveness in CD patients to anti-TNF-α therapy by sensitizing pathogenic T cells in the gastrointestinal tract to anti-TNF-α-mediated apoptosis. Experimental data from immune cells isolated from the gastrointestinal tract of patients with TNF-resistant Crohn's disease show that these cells spontaneously release IL-1β, which can be inhibited by the addition of an NLRP3 antagonist. It would be expected that NLRP3 inflammasome antagonists - in part by blocking IL-1β secretion - would inhibit the mechanism leading to anti-TNF unresponsiveness by re-sensitizing the patient to anti-TNF therapy. In patients with IBD who are naive to anti-TNF therapy, treatment with an NLRP3 antagonist would be expected to prevent primary and secondary unresponsiveness by blocking the mechanism leading to nonresponse.

[009] NLRP3 antagonists that are effective locally in the gastrointestinal tract may be effective drugs to treat IBD; in particular, in the treatment of TNF-resistant CD alone or in combination with anti-TNF therapy. Systemic inhibition of both IL-1β and TNF-α has been shown to increase the risk of opportunistic infections (Genovese MC et al, Arthritis Rheum 2004;50:1.412), so only blocking the NLRP3 inflammasome at the site of inflammation could reduce the risk of infection inherent in the neutralization of both IL-1β and TNF-α. NLRP3 antagonists that are potent in NLRP3 inflammasome-triggered cytokine secretion assays in cells, but have low in vitro permeability in a permeability assay, such as an MDCK assay, have poor systemic bioavailability in an experiment. pharmacokinetics of rat or mouse, but high levels of the compound in the colon and/or small intestine could be a useful therapeutic option for purposes restricted to the gastrointestinal tract.

[0010] The present invention also provides alternative therapies for the treatment of inflammatory or autoimmune diseases, including

IBD, which address the above problems associated with anti-TNFα agents.

SUMMARY

[0011] This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal and/or drug combination of the compound) which are useful, for example, to treat a condition, disease, or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, for example, a condition, disease, or disorder associated with NLRP3 signaling).

[0012] In some embodiments, a compound of Formula AA R3(R6)o is provided herein.

HN O O (R7)p (R1)m S B

A N N

H(R2)n Formula AA or a pharmaceutically acceptable salt thereof, wherein the variables in Formula AA may be as defined elsewhere herein.

[0013] This disclosure also presents compositions, as well as other methods of using and manufacturing them.

[0014] The present invention also relates to the Applicant's finding that inhibition of NLRP3 inflammasomes can increase an individual's sensitivity to an anti-TNFα agent or can overcome resistance to an anti-TNFα agent in an individual or , in fact, provide an alternative therapy to anti-TNFα agents.

[0015] Methods for treating an individual are provided herein which include: (a) identifying an individual who has a cell that has an elevated level of NLRP3 inflammasome activity and/or expression compared to a reference level; and (b) administering to the identified subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0016] Methods for treating inflammatory or autoimmune disease, including IBD, such as UC and CD in a subject in need thereof, which comprises administering to said subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or cocrystal thereof, wherein the NLRP3 antagonist is an NLRP3 antagonist that targets the gastrointestinal tract.

[0017] Methods for treating an individual in need thereof are provided herein which include: (a) identifying an individual who has resistance to an anti-TNFα agent; and (b) administering a treatment comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or cocrystal thereof to the identified subject.

Methods for treating a subject in need thereof are provided herein which include: administering a treatment comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or cocrystal thereof to an individual identified as having resistance to an anti-TNFα agent.

[0019] Methods for selecting a treatment for an individual in need thereof are provided herein which include: (a) identifying an individual who has resistance to an anti-TNFα agent; and (b) selecting for the identified individual a treatment that comprises a therapeutically effective amount of a compound of Formula I, or a pharmaceutically-preserved salt, solvate or cocrystal.

acceptable mind of the same.

[0020] Methods for selecting a treatment for a subject in need thereof are provided herein which include: selecting a treatment which comprises a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or cocrystal acceptable level of the same for an individual identified as having resistance to an anti-TNFα agent.

[0021] In some embodiments of any of the methods described herein, the treatment further includes a therapeutically effective amount of an anti-TNFα agent in addition to the NLRP3 antagonist.

[0022] An NLRP3 "antagonist" includes compounds that inhibit the ability of NLRP3 to induce the production of IL-1β and/or IL-18 by directly binding to NLRP3 or by inactivating, destabilizing, altering the distribution of NLRP3 or otherwise.

[0023] In one aspect, pharmaceutical compositions are provided that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.

[0024] In one aspect, methods are provided for modulating (e.g., agonizing, partially agonizing, antagonizing) the activity of NLRP3 that include contacting NLRP3 with a chemical entity described herein (e.g., a compound described herein). generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, for example, contacting a sample that includes one or more cells comprising NLRP3, as well as in vivo methods.

[0025] In a further aspect, methods of treating a disease are provided, wherein NLRP3 signaling contributes to pathology and/or symptoms and/or disease progression, which include administration to a subject in need of such treatment. of an effective amount of a chemical entity described herein (for example, a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

[0026] In a further aspect, methods of treatment are provided that include administering to a subject a chemical entity described herein (e.g., a compound described herein generically or specifically or a pharmaceutically acceptable salt thereof or compositions thereof). containing the same), wherein the chemical entity is administered in an amount effective to treat a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or disease progression, thereby treating the disease.

[0027] Modalities may include one or more of the following features.

[0028] The chemical entity may be administered in combination with one or more additional therapies with one or more agents suitable for treating the condition, disease or disorder.

[0029] Examples of indications that may be treated by the compounds disclosed herein include, but are not limited to, metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, in addition to central nervous system disorders such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson's disease, lung diseases such as asthma and COPD and idiopathic pulmonary fibrosis, liver diseases such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic diseases

cases such as acute and chronic pancreatitis, kidney disease such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, of vessels such as giant cell arteritis, bone disorders such as osteoarthritis, osteoporosis and osteopetrosis disorders, eye disease such as glaucoma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroiditis, Addison's disease, pernicious anemia, cancer and aging.

[0030] The methods may also include identifying the individual.

[0031] Other embodiments include those described in the Detailed Description and/or the claims. Additional Settings

[0032] To facilitate understanding of the disclosure presented in this document, several additional terms are defined below. In general, the nomenclature used herein and in laboratory procedures in organic chemistry, medical chemistry and pharmacology described herein is that which is well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by a person of ordinary skill in the art to which this disclosure pertains. Each of the patents, applications, published applications and other publications mentioned throughout the specification and appendices herewith is incorporated herein by reference in its entirety.

[0033] As used herein, the term "NLRP3" shall include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, if

complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, variants, derivatives, splicing variants, alleles, different species and active fragments thereof.

[0034] The term "acceptable" in relation to a formulation, composition or ingredient, as used herein, means having no persistent harmful effect on the general health of the individual being treated.

[0035] "API" refers to an active pharmaceutical ingredient.

[0036] The terms "effective amount" or "therapeutically effective amount", as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound that exhibits activity as an NLRP3 modulator, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof) which, if administered, will alleviate to some extent one or more of the symptoms of the disease or condition being treated. The result includes the reduction and/or alleviation of the signs, symptoms or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is that amount of the composition comprising a compound, as disclosed herein, necessary to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0037] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle, such as a solid or liquid filler, diluent, vehicle, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation.

ca and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, proportionate to a reasonable benefit/risk balance. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0038] The term "pharmaceutically acceptable salt" may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. In certain cases, pharmaceutically acceptable salts are obtained by reacting a compound described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term "pharmaceutically acceptable salt" may also refer to pharmaceutically acceptable addition salts prepared by reacting a compound having an acid group with a base to form a salt, such as an ammonium salt, a salt of alkali metal, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, a salt of organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl )methylamine and salts with amino acids such as arginine, lysine and the like, or by other methods previously determined. The pharmacologically acceptable salt is not specifically limited as long as it can be used in medicines. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases, such as sodium, potassium, magnesium, calcium and aluminum; their salts with organic bases, such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids, such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid: organics such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0039] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents. agents, suspending agents and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. There are various techniques for administering a compound in the art, including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0040] The term "individual" refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, mouse or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

[0041] The terms "to treat", "that treats" and "treatment", in the context of treating a disease or disorder, shall include the alleviating or relieving a disorder, disease or condition, or one or more of the symptoms associated with the disorder, disease or condition; or to delay the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

[0042] The term "prevent", "which prevents" or "prevention" in connection with a disease or disorder refers to the prophylactic treatment of an individual who is at risk of developing a condition (e.g., disease or disorder). specific or clinical symptom of the same), resulting in a decrease in the probability that the individual will develop the condition.

[0043] The terms "hydrogen" and "H" are used interchangeably in this document.

[0044] The term "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0045] The term "alkyl" refers to a hydrocarbon chain which may be a straight chain or branched chain, saturated or unsaturated, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group can have from 1 to 10 carbon atoms (inclusive) in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

[0046] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by an independently selected halo.

[0047] The term "alkoxy" refers to an -O-alkyl radical (eg -OCH3).

[0048] The term "carbocyclic ring", as used herein, includes an aromatic or non-aromatic cyclic hydrocarbon group having 3 to 10 carbons unless otherwise indicated, such as 3 to 8 carbons, such as 3 to 7 carbons, which may be optionally substituted. Carbocyclic rings can be monocyclic or bicyclic and, when bicyclic, can be fused bicyclic, bridged bicyclic or spirocyclic. Examples of carbocyclic rings include five membered, six membered and seven membered carbocyclic rings.

[0049] The term "heterocyclic ring" refers to a 5 to 8 membered monocyclic, 8 to 12 membered bicyclic or 11 to 14 membered aromatic or non-aromatic tricyclic ring system that has 1 to 3 heteroatoms, if monocyclic, 1 to 6 heteroatoms, if bicyclic, or 1 to 9 heteroatoms, if tricyclic, said heteroatoms selected from O, N or S (e.g. carbon atoms and 1 to 3, 1 to 6 or 1 to 9 heteroatoms of N, O or S, whether monocyclic, bicyclic or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. When heterocyclic rings are bicyclic or tricyclic, any two connected rings of the bicycle or tricycle may be fused bicyclic, bridged bicyclic, or spirocyclic. Examples of heterocyclic rings include five membered, six membered and seven membered heterocyclic rings.

[0050] The term "cycloalkyl", as used herein, includes a non-aromatic cyclic, bicyclic, fused or spiro hydrocarbon radical having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 10 carbons. 7 carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyls include five-membered, six-membered and seven-membered rings. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl.

[0051] The term "heterocycloalkyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic non-aromatic ring radical that has 1 to 3 heteroatoms, if monocyclic, 1 to 6 heteroatoms

atoms, if bicyclic, or 1 to 9 heteroatoms, if tricyclic, said heteroatoms selected from O, N or S (for example, carbon atoms and 1 to 3, 1 to 6 or 1 to 9 heteroatoms of N, O or S, if monocyclic, bicyclic or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkyl include five membered, six membered and seven membered heterocyclic rings. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like.

[0052] The term "aryl" is intended to mean an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.

[0053] The term "heteroaryl" is intended to mean an aromatic ring system containing 5 to 14 aromatic ring atoms which may be a single ring, two fused rings or three fused rings, wherein at least one aromatic ring atom is a heteroatom selected from, but not limited to, the group consisting of O, S and N. Examples include furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrimidinyl. Examples also include carbazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinidyl, carbazolyl, acrazyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran and the like.

[0054] The term "hydroxy" refers to an OH group.

[0055] The term "amino" refers to an NH2 group.

[0056] The term "oxo" refers to O. By way of example, the substitution of a CH2 group for oxo gives a C=O group.

[0057] As used herein, the terms "the A ring" or "A" are used interchangeably to denote in the formula AA, where the bond which is shown to be broken by the wavy line connects A to the S( O)(NHR3)=N of Formula AA.

[0058] As used herein, the terms "the A' ring" or "A'" are used interchangeably to denote in the formula AA-1, where the bond which is shown to be broken by the wavy line connects A' to the chemical moiety S(O)(NHR3)=N of Formula AA-1.

[0059] As used herein, the terms "ring A''" or "A''" are used interchangeably to denote in formula AA-2, formula AA-3 and formula AA-4, in that the bond which is shown to be broken by the wavy line connects A'' to the S(O)(NHR3)=N portion of formula AA-2, formula AA-3 and formula AA-4.

[0060] As used herein, the terms "the ring B" or "B" are used interchangeably to denote in the formula AA, where the bond which is shown to be broken by the wavy line connects B to the group NHC(O) of Formula AA.

[0061] As used herein, the terms "the ring

B'" or "B'" are used interchangeably to denote in formula AA-4, where the bond which is shown to be broken by the wavy line connects B' to the NHC(O) group of Formula AA-4.

[0062] As used herein, the terms "the B'' ring" or "B'' are used interchangeably to denote in the formula AA-5, where the bond which is shown to be broken by the wavy line connects B'' to the NHC(O) group of Formula AA-5.

[0063] As used herein, the term "the optionally substituted ring A" is used to denote in formula AA, where the bond that is shown to be broken by the wavy line connects A to the chemical moiety S(O)(NHR3) )=N of Formula AA.

[0064] As used herein, the term "the optionally substituted ring A'" is used to denote in the formula AA-1, wherein the bond that is shown to be broken by the wavy line connects A' to the chemical moiety S( O)(NHR3)=N of Formula AA-1.

[0065] As used herein, the term "the optionally substituted ring A''" is used to denote in formula AA-2, formula AA-3 and formula AA-4, wherein the bond which is shown as being broken by the wavy line connects A'' to the chemical moiety S(O)(NHR3)=N of Formula AA-2, formula AA-3 or formula AA-4.

[0066] As used herein, the term "the substituted ring B" is used to denote in formula AA and formula AA-1, wherein the bond which is shown to be broken by the wavy line connects B to the NHC group( O) of Formula AA and Formula AA-1.

[0067] As used herein, the term "the substituted ring B'" is used to denote in the formula AA-4, where the bond that is shown to be broken by the wavy line connects B' to the NHC group( O) of Formula AA-4.

[0068] As used herein, the term "the substituted ring B''" is used to denote in the formula AA-5, where the bond which is shown to be broken by the wavy line connects B'' to the group NHC(O) of Formula AA-5.

[0069] As used herein, the mention of "S(O2)", alone or as part of a larger mention, refers to the group .

[0070] Additionally, the atoms constituting the compounds of the present embodiments are designed to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C.

[0071] The scope of the compounds disclosed in the present document includes the tautomeric form of the compounds. Thus, by way of example, a compound which is represented as containing the chemical moiety is also intended to include the tautomeric form which contains the chemical moiety.

. Additionally, by way of example, a compound which is represented as containing the chemical moiety is also intended to include the tautomeric form which contains the chemical moiety.

[0072] Exemplified non-limiting compounds of the formulas described herein include a stereogenic sulfur atom and, optionally, one or more stereogenic carbon atoms. This disclosure provides examples of mixtures of stereoisomers (eg, racemic or scalemic mixture of enantiomers; mixture of diastereomers). This disclosure also describes and exemplifies methods for separating individual components of said mixtures of stereoisomers (e.g. resolving the enantiomers of a racemic mixture). In the case of compounds containing only one stereogenic sulfur atom, the separate enantiomers are represented graphically using one of the following two formats: formulas A/B (three-dimensional representation with hatch and solid triangular body); and formula C ("planar structures with stereogenic sulfur identified with *).

Formula A Formula B

R3 (R 6) o

HN O O (R 7)p * (R 1)m S B

A N N

H (R2)n Formula C

[0073] In reaction schemes showing the resolution of a racemic mixture, Formulas A/B and C are only intended to convey that the constituent enantiomers have resolved into the pure enantiopure form (about 98% ee or more) . Schemes showing resolution products using the A/B formula format are not intended to disclose or imply any correlation between absolute configuration and elution order.

[0074] Analogous formulas are used for compounds containing both stereogenic carbon and sulfur atoms.

[0075] Some of the compounds shown in the tables below are plotted using the formula A/B format. However, unless otherwise indicated (e.g., when the compound is synthesized from enantiomerically enriched starting materials (see, e.g., Compound 964a, Example 573), the stereogenic center is assigned based on starting materials), the stereochemistry depicted in sulfur shown for each of the compounds tabulated in formula A/B format is a tentative assignment and based, by analogy, on the absolute stereochemistry assigned to compound 162bb at present document (see Figure 5).

[0076] In some embodiments, for two enantiomers or two epimers of compounds of Formula AA that differ in stereochemical configuration at the sulfur atom of the chemical moiety S(O)NHR3(=N), one of the two enantiomers or epimers has antagonist activity. NLRP3 higher than the other.

[0077] In certain embodiments, when R3=H, for two enantio-

One or two epimers of compounds of Formula AA that differ in stereochemical configuration at the sulfur atom of the chemical moiety S(O)NHR3(=N), the enantiomer or epimer with stereochemical (R) configuration at the sulfur atom has antagonist activity of NLRP3 greater than the enantiomer or epimer with stereochemical (S) configuration at the sulfur atom. For example, the enantiomer or epimer with stereochemical configuration (R) at the sulfur atom exhibits a lower IC50 value in the hTHP-1 assay described herein.

[0078] Details of one or more embodiments of the invention are presented in the accompanying drawings and in the description below. Other features and advantages of the invention will be apparent from the description and drawings and from the claims.

DESCRIPTION OF THE FIGURES

[0079] Figure 1: Expression levels of RNA encoding NLRP3 in Crohn's disease patients who are responsive and unresponsive to infliximab.

[0080] Figure 2: Expression levels of RNA encoding IL-1β in patients with Crohn's disease who are responsive and unresponsive to infliximab.

[0081] Figure 3: Expression levels of RNA encoding NLRP3 in patients with Ulcerative Colitis (UC) who are responsive and unresponsive to infliximab.

[0082] Figure 4: Expression levels of RNA encoding IL-1β in patients with Ulcerative Colitis (UC) who are responsive and unresponsive to infliximab.

[0083] Figure 5 presents sphere and rod representations of two crystallographically independent molecules of compound 162bb in the asymmetric unit.

DETAILED DESCRIPTION

[0084] In one aspect, there is provided herein a compound of Formula AA R3(R6)o

HN O O (R7)p 1 S B (R )m

A N N

H(R2)n Formula AA wherein m = 0, 1 or 2; n = 0, 1 or 2; o = 1 or 2; p = 0, 1, 2 or 3; wherein the sum of o and p is 1 to 4; wherein A is a 5- to 10-membered heteroaryl or a C6-C10 aryl; B is a 6-membered heteroaromatic ring containing 1 to 3 N atoms, or an N-oxide thereof; wherein at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA; R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5 , SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(heter 5- to 10-membered aryl) and OCO (3- to 7-membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy , -O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connected thereto, independently form at least one C4-C12 monocyclic or bicyclic carbocyclic ring or at least one monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein: a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents. each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally and substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxy, oxo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl , CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, in that R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9 , 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl),

OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more of hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, NH, NR13 and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl , C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C=NR13)NR11R12, S(O2)C1- C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted by one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl,

3- to 7-membered heterocycloalkyl or NR11R12; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached, wherein the ring is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R13 is C1-C6 alkyl, C1-C6 haloalkyl or -(Z1-Z2)a1-Z3; each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl and -(Z1-Z2)a1-Z3; a1 is an integer selected from 0 to 10 (eg 0 to 5); each Z1 is independently C1-C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; each Z2 is independently a bond, NH, N(C1-C6 alkyl), -O-, -S- or 5- to 10-membered heteroarylene; Z3 is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with a or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R3 is selected from hydrogen, cyano, hydroxy, CO2Cl-

C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl, wherein the C1-C2 alkylene group is optionally substituted by oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or monocyclic or bicyclic C6-C10 aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted by 1 or 2 R6; R15 is -(Z4-Z5)a2-Z6; a2 is an integer selected from 1 to 10 (eg 1 to 5 (eg 2 to 5)); each Z4 is independently selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-; provided that the Z4 group bonded directly to R1 or R2 is -O- or -S-; each Z5 is independently C1 -C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; and Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy) or an optionally substituted group selected from the group consisting of: C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each one of which is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) ) and hydroxy; provided that the compound of Formula AA is not a compound selected from the group consisting of:

, ,

HN H N N Y Y N The O

HO , F , H2N H H N N H2N N

No O S N O S N O O O O

HO HO , and

H H2N N

No Y Y N The O

HOF; or a pharmaceutically acceptable salt thereof.

[0085] In one aspect, there is provided herein a compound of Formula AA: R3(R6)o

HN O O (R7)p 1 S B (R )m

A N N

H(R2)n Formula AA wherein m = 0, 1 or 2; n = 0, 1 or 2; o = 1 or 2; p = 0, 1, 2 or 3; wherein the sum of o and p is 1 to 4; wherein A is a 5- to 10-membered heteroaryl or a C6-C10 aryl; B is a 6-membered heteroaromatic ring containing 1 to 3 N atoms, or an N-oxide thereof;

wherein at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA; R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5 , SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(heter 5- to 10-membered aryl) and OCO (3- to 7-membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy , -O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, considered together with the atoms connected to them, independently-

form at least one C4-C12 monocyclic or bicyclic carbocyclic ring or at least one monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein: a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents. each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally and substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,

halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl members), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl , C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1- C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl , OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more of hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from among O, NH, NR13 and

S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C=NR13)NR11R12, S(O2)C1- C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted by one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR11R12; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached, wherein the ring is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R13 is C1-C6 alkyl, C1-C6 haloalkyl or -(Z1-Z2)a1-Z3; each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl and -(Z1-Z2)a1-Z3; a1 is an integer selected from 0 to 10 (eg 0 to 5); each Z1 is independently C1-C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; each Z2 is independently a bond, NH, N(C1-C6 alkyl), -O-, -S- or 5- to 10-membered heteroarylene; Z3 is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with a or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R3 is selected from hydrogen, cyano, hydroxy, CO2Cl-

C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl, wherein the C1-C2 alkylene group is optionally substituted by oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or monocyclic or bicyclic C6-C10 aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted by 1 or 2 R6; R15 is -(Z4-Z5)a2-Z6; a2 is an integer selected from 1 to 10 (eg 1 to 5 (eg 2 to 5)); each Z4 is independently selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-; provided that the Z4 group bonded directly to R1 or R2 is -O- or -S-; each Z5 is independently C1 -C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; and Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy) or an optionally substituted group selected from the group consisting of: C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloal-

alkyl, 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; provided that the compound of Formula AA is not a compound selected from the group consisting of: , ,

HN H N N Y Y N The O

HO , F , H 2N H H N N H2N N

No O S N O S N O O O O

HO HO , and

H H2N N

No Y Y N The O

HOF; or a pharmaceutically acceptable salt thereof.

[0086] In one aspect, there is provided herein a compound of Formula AA

R3 (R6) o

HN O O (R7)p (R1)m S B

A N N

H(R2)n Formula AA wherein m = 0, 1 or 2; n = 0, 1 or 2; o = 1 or 2; p = 0, 1 2, or 3; wherein the sum of o and p is 1 to 4; wherein A is a 5- to 10-membered heteroaryl or a C6-C10 aryl; B is a 6-membered heteroaromatic ring containing 1 to 3 N atoms, or an N-oxide thereof; wherein at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA; R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO (5 to 10 membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), C6 -C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(heterocycloalkyl with 3 to 7 members), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl,

C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl , 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO( 5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S( O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring

co includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms)- linked to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6 -C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 to alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1- C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl , wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-

C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(3 to 7 membered heterocycloalkyl members), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, (C=NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12 , COR13,

CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl ; or R8 and R9, together with the nitrogen to which they are attached, form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached; R13 is C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl or 5- to 10-membered heteroaryl; each of R11 and R12 at each occurrence is independently selected from hydrogen and C1-C6 alkyl; and R3 is selected from hydrogen, cyano, hydroxy, CO2Cl-

C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl, wherein the C1-C2 alkylene group is optionally substituted by oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or monocyclic or bicyclic C6-C10 aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted by 1 or 2 R6; provided that the compound of Formula AA is not a compound selected from the group consisting of:

, ,

HN H N N Y Y N The O HO , F ,

H H2N N H2N

H N N N O S N S The No. O O O O

HO HO , and H2N H

N N Y Y N The O

HOF; or a pharmaceutically acceptable salt thereof.

[0087] In another aspect, there is provided herein a compound of Formula AA R3(R6)o

HN O O (R7)p 1 S B (R )m

A N N

H (R2)n Formula AA wherein the compound of Formula AA is selected from R3 (R6'')o

HN O O (R7)p 1 B (R )m S A' N N

H(R2)n (Formula AA-1),

R3 (R 6) o

HN O O (R 7)p 1 B (R )m' S A'' N N

H (R2)n' (Formula AA-2), R3 (R6)o

HN O O (R7)p 1' B (R )m'' S A'' N N

H (R2')n'' (Formula AA-3), R3 (R6)o

HN O O (R7)p 1 B' (R )m''' S A'' N N

H (R2'')n''' (Formula AA-4) and (R6')o H 2N O O (R 7') p 1 S B'' (R ) m''' S

N N

H (R 2'') n''' (Formula AA-5), wherein m = 0, 1 or 2; n = 0, 1 or 2; m' = 0, 1 or 2; n' = 0, 1 or 2; wherein the sum of m' and n' is 0, 1 or 3; m'' = 0, 1 or 2; n'' = 0, 1 or 2; where the sum of m'' and n'' is 2; m''' = 1; n''' = 1; o = 1 or 2; p = 0, 1, 2 or 3; wherein the sum of o and p is 1 to 4; on what

A' is selected from: a 6- to 10-membered heteroaryl, a C6-C10 aryl, a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)=N ; A'' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)=N; B is a 6-membered heteroaromatic ring containing 1 to 3 N atoms, or an N-oxide thereof; B' is 2-pyridyl, 3-pyridyl or an N-oxide thereof; B'' is 4-pyridyl or an N-oxide thereof; wherein at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-2, Formula AA-3 and Formula AA-4; at least one R6' is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-5; at least one R6'' is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-1; R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl),

OCO(3 to 7 membered heterocycloalkyl), C6-C10 aryl, 5 to 10 membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S( O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, heteroaryl with 5 to 10 membered, C3-C7 cycloalkyl and 3 to 7 membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy , R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl) 10 members) and OCO(3 to 7 membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy , -O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connected thereto, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein: a ) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O,

NH, NR13 , S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents. each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally and substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R1' and R2' are each independently selected from C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl, Br, I, CN, NO2, CO2C1-C6 alkyl, CO2C3- C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NR8R9, C(O )R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C2-C6 alkyl, the C1-C6 alkoxy, the C1-C6 haloalkyl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, the C3-C7 cycloalkyl, and the 3- to 7-membered heterocycloalkyl are optionally substituted - with one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 7 membered, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl) and OCO(3 to 7 membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1' or R2' C3-C7 cycloalkyl or the 3- to 7-membered R1' or R2' heterocycloalkyl is further optionally substituted independently by one to three hydroxy, -O(C0 -C3 alkylene)C6 -C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1' and R2' on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1 -C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloal-

alkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5-10-membered heteroaryl, the C3-C10 cycloalkyl and the 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl , C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R2'' is F or CH3; or when the compound of Formula AA is a compound of Formula AA-4, a pair of R1 and R2'' on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C12 carbocyclic ring monocyclic or bicyclic or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 , and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl , C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, ah 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-

C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxy, oxo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl , CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, in that R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9 , 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl The; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more of hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 unbranched alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxy, oxo, CN, NO2, COC1-C6 alkyl, CO2C1- C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl , wherein R6' and R7' are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 to 7 membered, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), C6 -C10 aryloxy and S(O2)C1-C6 alkyl ; and wherein the C1-C6 alkoxy by which R6' or R7' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6' or R7' is optionally fused to a carbocyclic ring or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more independently selected substituents among hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6'' is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxy, oxo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6'' is optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2) C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6'' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6'' is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6'' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more independently selected substituents among hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C=NR13)NR11R12, S(O2)C1- C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted by one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR11R12; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached, wherein the ring is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R13 is C1-C6 alkyl, C1-C6 haloalkyl or -(Z1-Z2)a1-Z3; each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl and -(Z1-Z2)a1-Z3; a1 is an integer selected from 0 to 10 (eg 0 to 5); each Z1 is independently C1-C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; each Z2 is independently a bond, NH, N(C1-C6 alkyl), -O-, -S- or 5- to 10-membered heteroarylene; Z3 is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with a or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R3 is selected from hydrogen, cyano, hydroxy, CO2Cl-

C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl, wherein the C1-C2 alkylene group is optionally substituted by oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl, or heteroaryl is optionally inde-

pendantly substituted by 1 or 2 R6; R15 is -(Z4-Z5)a2-Z6; a2 is an integer selected from 1 to 10 (eg 1 to 5 (eg 2 to 5)); each Z4 is independently selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-; provided that the Z4 group bonded directly to R1 or R2 is -O- or -S-; each Z5 is independently C1 -C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; and Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy) or an optionally substituted group selected from the group consisting of: C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each one of which is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) ) and hydroxy; or a pharmaceutically acceptable salt thereof.

[0088] In another aspect, there is provided herein a compound of Formula AA: R3(R6)o

HN O O (R7)p 1 S B (R )m

A N N

H(R2)n Formula AA wherein the compound of Formula AA is selected from among

R3 (R6'')o

HN O O (R7)p 1 S B (R )m A' N N

H (R2)n (Formula AA-1), R3 (R 6)o

HN O O (R7)p 1 S B (R )m' A'' N N

H (R2)n' (Formula AA-2), R3 (R6)o

HN O O (R7)p 1' S B (R )m'' A'' N N

H (R2')n'' (Formula AA-3), R3 (R6)o

HN O O (R7)p 1 S B' (R )m''' A'' N N

H (R2'' )n''' (Formula AA-4) and (R6' )o H 2N O O (R 7') p 1 B'' (R )m''' S S

N N

H (R 2'') n''' (Formula AA-5), wherein m = 0, 1 or 2; n = 0, 1 or 2; m' = 0, 1 or 2; n' = 0, 1 or 2; wherein the sum of m' and n' is 0, 1 or 3; m'' = 0, 1 or 2; n'' = 0, 1 or 2; where the sum of m'' and n'' is 2; m''' = 1;

n''' = 1; o = 1 or 2; p = 0, 1, 2 or 3; wherein the sum of o and p is 1 to 4; wherein A' is selected from: a 6- to 10-membered heteroaryl, a C6-C10 aryl, a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3) =N; A'' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)=N; B is a 6-membered heteroaromatic ring containing 1 to 3 N atoms, or an N-oxide thereof; B' is 2-pyridyl, 3-pyridyl or an N-oxide thereof; B'' is 4-pyridyl or an N-oxide thereof; wherein at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-2, Formula AA-3 and Formula AA-4; at least one R6' is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-5; at least one R6'' is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-1;

R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5 , SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(heter 5- to 10-membered aryl) and OCO (3- to 7-membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy , -O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connected thereto, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring,

wherein: a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents. each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally and substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R1' and R2' are each independently selected from C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl, Br, I, CN, NO2, CO2C1-C6 alkyl, CO2C3- C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl),

OCO(3 to 7 membered heterocycloalkyl), C6-C10 aryl, 5 to 10 membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S( O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C2-C6 alkyl, the C1-C6 alkoxy, the C1-C6 haloalkyl, the C6-C10 aryl , 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1- C6 alkyl, C1-C6 alkoxy, R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl , OCO(5 to 10 membered heteroaryl) and OCO(3 to 7 membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1' or R2' C3-C7 cycloalkyl or the 3- to 7-membered R1' or R2' heterocycloalkyl is further optionally substituted independently by one to three hydroxy, -O(C0 -C3 alkylene)C6 -C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1' and R2' on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1 -C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, the C3-C10 cycloalkyl, and the heterocyl 3- to 10-membered chloroalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R2'' is F or CH3; or when the compound of Formula AA is a compound of Formula AA-4, a pair of R1 and R2'' on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C12 carbocyclic ring monocyclic or bicyclic or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 , and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl , C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, ah 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1- C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl , wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl ), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more of hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl;

or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hy - droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6' and R7' are each independently selected from C1-C6 unbranched alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl , CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, in wherein R6' and R7' are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3 to 7 membered, C6-C10 aryl, 5-10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy by which R6' or R7' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6' or R7' is optionally fused to a carbocyclic ring or a heterocyclic ring

a five- to seven-membered ring containing one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more independently selected substituents among hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6'' is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl )2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6'' is optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, hetero-

5- to 10-membered aryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl ; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6'' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6'' is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6''' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C=NR13)NR11R12, S(O2)C1- C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted by one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR11R12; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached, wherein the ring is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R13 is C1-C6 alkyl, C1-C6 haloalkyl or -(Z1-Z2)a1-Z3; each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl and -(Z1-Z2)a1-Z3; a1 is an integer selected from 0 to 10 (for example, 0 to 5); each Z1 is independently C1-C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; each Z2 is independently a bond, NH, N(C1-C6 alkyl), -O-, -S- or 5- to 10-membered heteroarylene; Z3 is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with a or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R3 is selected from hydrogen, cyano, hydroxy, CO2Cl-

C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl, wherein the C1-C2 alkylene group is optionally substituted by oxo;

R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or monocyclic or bicyclic C6-C10 aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted by 1 or 2 R6; R15 is -(Z4-Z5)a2-Z6; a2 is an integer selected from 1 to 10 (eg 1 to 5 (eg 2 to 5)); each Z4 is independently selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-; provided that the Z4 group bonded directly to R1 or R2 is -O- or -S-; each Z5 is independently C1 -C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; and Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy) or an optionally substituted group selected from the group consisting of: C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each one of which is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) ) and hydroxy; or a pharmaceutically acceptable salt thereof.

[0089] In another aspect, a compound of Formula AA is described herein

R3 (R6) o

HN O O (R7)p (R1)m S B

A N N

H (R2)n Formula AA wherein the compound of Formula AA is selected from R3 (R6'' )o

HN O O (R7)p 1 S B (R )m A' N N

H (R2)n (Formula AA-1), R3 (R 6)o

HN O O (R 7)p 1 S B (R )m' A'' N N

H (R2)n' (Formula AA-2), R3 (R6)o

HN O O (R7)p 1' S B (R )m'' A'' N N

H (R2')n'' (Formula AA-3), R3 (R6)o

HN O O (R7)p 1 S B' (R )m''' A'' N N

H (R2'' )n''' (Formula AA-4) and (R6' )o H 2N O O (R7')p 1 S B'' (R )m''' S

N N

H(R 2'')n''' (Formula AA-5), wherein m = 0, 1 or 2; n = 0, 1 or 2; m' = 0, 1 or 2; n' = 0, 1 or 2; wherein the sum of m' and n' is 0, 1 or 3; m'' = 0, 1 or 2; n'' = 0, 1 or 2; where the sum of m'' and n'' is 2; m''' = 1; n''' = 1; o = 1 or 2; p = 0, 1 2, or 3; wherein the sum of o and p is 1 to 4; wherein A' is selected from: a 6- to 10-membered heteroaryl, a C6-C10 aryl, a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3) =N; A'' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)=N; B is a 6-membered heteroaromatic ring containing 1 to

3 N atoms, or an N-oxide thereof; B' is 2-pyridyl, 3-pyridyl or an N-oxide thereof; B'' is 4-pyridyl or an N-oxide thereof; wherein at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-2, Formula AA-3 and Formula AA-4; at least one R6' is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-5; at least one R6'' is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-1; R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO (5 to 10 membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), C6 -C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(heterocycloalkyl with 3 to 7 members), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1 - C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl,

NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(3 to 7 membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S( O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or the heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1 -C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, heteroaryl with 5 to 10 mem-

bros, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl , C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R1' and R2' are each independently selected from C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl, Br, I, CN, NO2, COC1-C6 alkyl, CO- C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3-membered heterocycloalkyl 7-membered), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10-membered), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 3- to 7-membered alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and heterocycloalkyl, wherein the C2-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl and the 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) ,

NHCO(3- to 7-membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of R1' or R2' C3-C7 cycloalkyl or R1' or R2' 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy, halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1' and R2' on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C10 cycloalkyl, 3 to 10 membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and heterocycloalkyl 3- to 10-membered la are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo , NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9;

R2'' is F or CH3; or, when the compound of Formula AA is a compound of Formula AA-4, a pair of R1 and R2'' on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C12 ring monocyclic or bicyclic carbocyclic or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O) 2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3 -C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, heteroa 5- to 10-membered ryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl , C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1- C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl , wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl ), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(he 5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9;

R6' and R7' are each independently selected from C1-C6 unbranched alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl , CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, in wherein R6' and R7' are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3 to 7 membered, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heter 5- to 10-membered aryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein p C1-C6 alkoxy by which R6' or R7' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6' or R7' is optionally fused to a car ring - bocyclic or five- to seven-membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl;

or a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6'' is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl )2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6'' is optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5-10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) to 10 members), NHCO(3 to 3-member heterocycloalkyl 7 members), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6'' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6'' is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6'' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, (C=NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12 , COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl ; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached;

R13 is C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl or 5- to 10-membered heteroaryl; each of R11 and R12 at each occurrence is independently selected from hydrogen and C1-C6 alkyl; and R3 is selected from hydrogen, cyano, hydroxy, CO2C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, and wherein the C1-C2 alkylene group is optionally substituted by oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or monocyclic or bicyclic C6-C10 aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted by 1 or 2 R6; or a pharmaceutically acceptable salt thereof. The AA Formula

[0090] In some modalities, Formula AA is Formula AA-1 R3 (R6'')o

HN O O (R7)p 1 S B (R )m A' N N

H(R2)n (Formula AA-1).

[0091] In some embodiments, Formula AA is Formula AA-2 R3 (R6)o

HN O O (R7)p 1 S B (R )m' A'' N N

H(R2)n' (Formula AA-2).

[0092] In some modalities, Formula AA is Formula AA-3

R3 (R6) o

HN O O (R7)p 1' S B (R )m'' A'' N N

H(R2')n'' (Formula AA-3).

[0093] In some embodiments, Formula AA is Formula AA-4 R3 (R6)o

HN O O (R7)p 1 S B' (R )m''' A'' N N

H(R2'')n''' (Formula AA-4).

[0094] In some embodiments, the Formula AA is the Formula AA-5 (R6' )o H 2N O O (R7')p 1 S B'' (R )m''' S

N N

H(R 2'')n''' (Formula AA-5).

[0095] In some embodiments, the variables shown in the formulas in this document are as follows: The variables m, m', m'', n, n' and n''

[0096] In some modalities, m=0, 1 or 2.

[0097] In some modalities, m=0 or 1.

[0098] In some modalities, m=1 or 2.

[0099] In some modalities, m=0 or 2.

[00100] In some modes, m=0.

[00101] In some modes, m=1.

[00102] In some modalities, m=2.

[00103] In some modalities, n=0, 1 or 2.

[00104] In some modalities, n=0 or 1.

[00105] In some modalities, n=1 or 2.

[00106] In some modalities, n=0 or 2.

[00107] In some modalities, n=0.

[00108] In some modalities, n=1.

[00109] In some modalities, n=2.

[00110] In some modes, m=0 and n=0.

[00111] In some modes, m=1 and n=0.

[00112] In some modalities, m=1 and n=1.

[00113] In some embodiments of the compound of Formula, AA-1, m=1 and n=0.

[00114] In some embodiments of the compound of Formula, AA-1, m=1 and n=1.

[00115] In some modes, m'=0, 1 or 2.

[00116] In some modes, m'=0 or 1.

[00117] In some modes, m'=1 or 2.

[00118] In some modes, m'=0 or 2.

[00119] In some modes, m'=0.

[00120] In some modes, m'=1.

[00121] In some modes, m'=2.

[00122] In some embodiments, n'=0, 1, or 2.

[00123] In some modes, n'=0 or 1.

[00124] In some modalities, n'=1 or 2.

[00125] In some modes, n'=0 or 2.

[00126] In some modes, n'=0.

[00127] In some modes, n'=1.

[00128] In some modalities, n'=2.

[00129] In some modes, m'=0 and n'=0.

[00130] In some modes, m'=1 and n'=0.

[00131] In some modes, m'=2 and n'=1.

[00132] In some modes, m'=1 and n'=2.

[00133] Where the sum of m' and n' is 0, 1, or 3.

[00134] In some embodiments of the compound of Formula, AA-2, m'=1 and n'=0.

[00135] In some modes, m''=0, 1 or 2.

[00136] In some modes, m''=0 or 1.

[00137] In some modes, m''=1 or 2.

[00138] In some modes, m''=0 or 2.

[00139] In some modes, m''=0.

[00140] In some modes, m''=1.

[00141] In some modes, m''=2.

[00142] In some modes, n''=0, 1 or 2.

[00143] In some modes, n''=0 or 1.

[00144] In some modes, n''=1 or 2.

[00145] In some modes, n''=0 or 2.

[00146] In some modes, n''=0.

[00147] In some modes, n''=1.

[00148] In some modes, n''=2.

[00149] In some modes, m''=0 and n''=2.

[00150] In some modes, m''=2 and n''=0.

[00151] In some modes, m''=1 and n''=1.

[00152] where the sum of m'' and n'' is 2.

[00153] In some embodiments of the compound of Formula, AA-3, m''=1 and n''=1. The A, A' and A'' Ring and substitutions in the A, A' and A'' Ring The A Ring

[00154] In some embodiments, A is a 5 to 10 membered heteroaryl or a C7-C10 aryl.

[00155] In some embodiments, A is a 5-membered heteroaryl.

[00156] In some embodiments, A is a heteroaryl with 6 to 10 members.

[00157] In some embodiments, A is a 6-membered heteroaryl.

[00158] In some embodiments, A is a C6-C10 aryl.

[00159] In some embodiments, A is a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1.

[00160] In some embodiments, A is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)=N .

[00161] In some embodiments, A is different from a chemical moiety selected from the group consisting of: pyrazolyl, 2-thiophenyl, 2-furanyl or phenyl monosubstituted by an R1 or R2 in the position ortho to the bond connecting the phenyl to the chemical moiety S(O)(NH).

[00162] In some embodiments, A is selected from the group consisting of: 3-furanyl, 3-thiophenyl, pyrrolyl, imidazoyl, triazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyrimidinyl, triazinyl, benzimidazolyl, benzothiophene, benzofuranyl , indazolyl, benzotriazolyl, quinolinyl, quinazolinyl and benzotriazinyl.

[00163] In some embodiments, A is thiophenyl.

[00164] In some embodiments, A is thiazolyl.

[00165] In some embodiments, A is pyrazolyl.

[00166] In some embodiments, A is imidazolyl.

[00167] In some embodiments, A is pyrrolyl.

[00168] In some embodiments, A is oxazolyl.

[00169] In some embodiments, A is furanyl.

[00170] In some embodiments, A is isoxazolyl.

[00171] In some embodiments, A is isothiazolyl.

[00172] In some embodiments, A is triazolyl (eg, 1,2,3-triazolyl or 1,2,4-triazolyl).

[00173] In some embodiments, A is pyridinyl.

[00174] In some embodiments, A is pyridimidinyl.

[00175] In some embodiments, A is pyrazinyl.

[00176] In some embodiments, A is pyridazinyl.

[00177] In some embodiments, A is triazinyl.

[00178] In some embodiments, A is phenyl.

[00179] In some embodiments, A is phenyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.

[00180] In some embodiments, A is naphthyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.

[00181] In some embodiments, A is furanyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 R2.

[00182] In some embodiments, A is furanyl optionally substituted with 1 R1 and optionally substituted with 1 or 2 R2.

[00183] In some embodiments, A is thiophenyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00184] In some embodiments, A is oxazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00185] In some embodiments, A is thiazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.

[00186] In some embodiments, A is oxazolyl optionally substituted with 2 R 1 or optionally substituted with 2 R 2 .

[00187] In some embodiments, A is thiazolyl optionally substituted with 2 R1 or optionally substituted with 2 R2.

[00188] In some embodiments, A is pyrazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00189] In some embodiments, A is pyrazolyl optionally substituted by 1 R1 and optionally substituted by 1 or 2 R2.

[00190] In some embodiments, A is pyrazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 R2.

[00191] In some embodiments, A is pyridyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.

[00192] In some embodiments, A is indazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00193] In some embodiments, A is imidazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00194] In some embodiments, A is pyrrolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.

[00195] In some embodiments, A is oxazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00196] In some embodiments, A is furanyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.

[00197] In some embodiments, A is isoxazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00198] In some embodiments, A is isothiazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00199] In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl) optionally substituted with 1 R 1 and optionally substituted with 1 R 2 .

[00200] In some embodiments, A is pyridinyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.

[00201] In some embodiments, A is pyridimidinyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00202] In some embodiments, A is pyrazinyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00203] In some embodiments, A is pyridazinyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.

[00204] In some embodiments, A is triazinyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2.

[00205] In some embodiments, A is phenyl substituted by 1 R1 and optionally substituted by 1 R2.

[00206] In some embodiments, A is naphthyl substituted with 1 R1 and optionally substituted with 1 R2.

[00207] In some embodiments, A is furanyl substituted with 1 R1 and optionally substituted with 1 R2.

[00208] In some embodiments, A is thiophenyl substituted by 1 R1 and optionally substituted by 1 R2.

[00209] In some embodiments, A is oxazolyl substituted by 1 R1 and optionally substituted by 1 R2.

[00210] In some embodiments, A is thiazolyl substituted by 1 R1 and optionally substituted by 1 R2.

[00211] In some embodiments, A is pyrazolyl substituted by 1 R1 and optionally substituted by 1 R2.

[00212] In some embodiments, A is pyridyl substituted by 1 R1 and optionally substituted by 1 R2.

[00213] In some embodiments, A is indazolyl optionally substituted by 1 R1 and optionally substituted by 1 R2.

[00214] In some embodiments, A is phenyl substituted by 1 R1 and substituted by 1 R2.

[00215] In some embodiments, A is furanyl substituted by 1 R1 and substituted by 1 R2.

[00216] In some embodiments, A is thiophenyl substituted by 1 R1 and substituted by 1 R2.

[00217] In some embodiments, A is oxazolyl substituted by 1 R1 and substituted by 1 R2.

[00218] In some embodiments, A is thiazolyl substituted by 1 R1 and substituted by 1 R2.

[00219] In some embodiments, A is pyrazolyl substituted by 1 R1 and substituted by 1 R2.

[00220] In some embodiments, A is pyridyl substituted by 1 R1 and substituted by 1 R2.

[00221] In some embodiments, A is imidazolyl substituted by 1

R1 and replaced by 1 R2.

[00222] In some embodiments, A is pyrrolyl substituted by 1 R1 and substituted by 1 R2.

[00223] In some embodiments, A is oxazolyl substituted by 1 R1 and substituted by 1 R2.

[00224] In some embodiments, A is furanyl substituted by 1 R1 and substituted by 1 R2.

[00225] In some embodiments, A is isoxazolyl substituted by 1 R1 and substituted by 1 R2.

[00226] In some embodiments, A is isothiazolyl substituted by 1 R1 and substituted by 1 R2.

[00227] In some embodiments, A is triazolyl (eg, 1,2,3-triazolyl or 1,2,4-triazolyl) substituted with 1 R1 and substituted with 1 R2.

[00228] In some embodiments, A is pyridimidinyl substituted by 1 R1 and substituted by 1 R2.

[00229] In some embodiments, A is pyrazinyl substituted by 1 R1 and substituted by 1 R2.

[00230] In some embodiments, A is pyridazinyl substituted by 1 R1 and substituted by 1 R2.

[00231] In some embodiments, A is triazinyl substituted by 1 R1 and substituted by 1 R2.

[00232] In some embodiments, A is phenyl, m is 0 or 1, and n is 0, 1 or 2.

[00233] In some embodiments, A is furanyl, m is 0 or 1, and n is 0, 1 or 2.

[00234] In some embodiments, A is thiophenyl, m is 0 or 1, and n is 0, 1 or 2.

[00235] In some embodiments, A is oxazolyl, m is 0 or 1, and n is 0, 1 or 2.

[00236] In some embodiments, A is thiazolyl, m is 0 or 1, and n is 0, 1 or 2.

[00237] In some embodiments, A is pyrazolyl, m is 0 or 1, and n is 0, 1 or 2.

[00238] In some embodiments, A is pyridyl, m is 0 or 1, and n is 0, 1 or 2.

[00239] In some embodiments, A is indazolyl, m is 0 or 1, and n is 0, 1 or 2.

[00240] In some embodiments, A is phenyl, m is 0, and n is 0 or 1.

[00241] In some embodiments, A is furanyl, m is 0, and n is 0 or 1.

[00242] In some embodiments, A is thiophenyl, m is 0, and n is 0 or 1.

[00243] In some embodiments, A is oxazolyl, m is 0, and n is 0 or

1.

[00244] In some embodiments, A is thiazolyl, m is 0, and n is 0 or 1.

[00245] In some embodiments, A is pyrazolyl, m is 0, and n is 0 or

1.

[00246] In some embodiments, A is pyridyl, m is 0, and n is 0 or 1.

[00247] In some embodiments, A is thiazolyl, m is 1, and n is 1.

[00248] In some embodiments, A is pyrazolyl, m is 1 or 2, and n is 1 or 2.

[00249] In some embodiments, A is imidazolyl, m is 1 or 2, and n is 1 or 2.

[00250] In some embodiments, A is pyrrolyl, m is 1 or 2, and n is 1 or 2.

[00251] In some embodiments, A is oxazolyl, m is 1, and n is 1.

[00252] In some embodiments, A is furanyl, m is 1 or 2, and n is 1 or 2.

[00253] In some embodiments, A is isoxazolyl, m is 1, and n is 1.

[00254] In some embodiments, A is isothiazolyl, m is 1, and n is 1.

[00255] In some embodiments, A is triazolyl (e.g.,

1,2,3-triazolyl or 1,2,4-triazolyl), m is 1, and n is 1.

[00256] In some embodiments, A is pyridinyl, m is 1 or 2, and n is 1 or 2.

[00257] In some embodiments, A is pyridimidinyl, m is 1 or 2, and n is 1 or 2.

[00258] In some embodiments, A is pyrazinyl, m is 1 or 2, and n is 1 or 2.

[00259] In some embodiments, A is pyridazinyl, m is 1 or 2, and n is 1 or 2.

[00260] In some embodiments, A is triazinyl, m is 1, and n is 1.

[00261] In some embodiments, A is one of the rings disclosed below optionally substituted as disclosed below, wherein, in each case, the bond that is shown to be broken by the wavy line connects A to the chemical moiety S(O)(NHR3) =N of Formula AA.

[00262] In some embodiments, the optionally substituted ring A( ) is .

[00263] In some embodiments, the optionally substituted ring A is .

[00264] In some embodiments, the optionally substituted ring A is .

[00265] In some embodiments, the optionally substituted ring A is .

[00266] In some embodiments, the optionally substituted ring

Hey.

[00267] In some embodiments, the optionally substituted ring A is .

[00268] In some embodiments, the optionally substituted ring A is .

[00269] In some embodiments, the optionally substituted ring A is .

[00270] In some embodiments, the optionally substituted ring R1

N Aé S .

[00271] In some embodiments, the optionally substituted ring A is .

[00272] In some embodiments, the optionally substituted ring

S R1 N Ae .

[00273] In some embodiments, the optionally substituted ring A is .

[00274] In some embodiments, the optionally substituted ring A is .

[00275] In some embodiments, the optionally substituted ring

Hey.

[00276] In some embodiments, the optionally substituted ring A is .

[00277] In some embodiments, the optionally substituted ring

S A is R1 .

[00278] In some embodiments, the optionally substituted ring A is .

[00279] In some embodiments, the optionally substituted ring A is .

[00280] In some embodiments, the optionally substituted ring R1

Oh.

[00281] In some embodiments, the optionally substituted ring

The Ae R1.

[00282] In some embodiments, the optionally substituted ring A is .

[00283] In some embodiments, the optionally substituted ring A is .

[00284] In some embodiments, the optionally substituted ring A is .

[00285] In some embodiments, the optionally substituted ring R2

the 1

R Aye.

[00286] In some embodiments, the optionally substituted ring R2

NH R1 Ae .

[00287] In some embodiments, the optionally substituted ring R2 R1

No.

[00288] In some embodiments, the optionally substituted ring A is .

[00289] In some embodiments, the optionally substituted ring A is .

[00290] In some embodiments, the optionally substituted ring

NH 1

R A is R2 .

[00291] In some embodiments, the optionally substituted ring A is .

[00292] In some embodiments, the optionally substituted ring A is .

[00293] In some embodiments, the substituted ring A is

S 1

R R2 .

[00294] In some embodiments, the substituted ring A is

The R1 R2 .

[00295] In some embodiments, the substituted ring A is

HN 1

R R2 . R2 R1

No

[00296] In some embodiments, the substituted ring A is .

[00297] In some embodiments, the substituted ring A is R2

N R1 .

[00298] In some embodiments, the optionally substituted ring A is .

[00299] In some embodiments, the optionally substituted ring R2 R1

HN Aé N .

[00300] In some embodiments, the optionally substituted ring

Hey.

[00301] In some embodiments, the optionally substituted ring A is .

[00302] In some embodiments, the optionally substituted ring A is .

[00303] In some embodiments, the optionally substituted ring A is .

[00304] In some embodiments, the optionally substituted ring R2

N R1 Ae N .

[00305] In some embodiments, the optionally substituted ring R1 R2

N Aé N .

[00306] In some embodiments, the optionally substituted ring R1

NH R2 A is N .

[00307] In some embodiments, the optionally substituted ring A is .

[00308] In some embodiments, the optionally substituted ring A is .

[00309] In some embodiments, the optionally substituted ring A is .

[00310] In some embodiments, the optionally substituted ring A is .

[00311] In some embodiments, the optionally substituted ring A is .

[00312] In some embodiments, the optionally substituted ring A is .

[00313] In some embodiments, the optionally substituted ring A is .

[00314] In some embodiments, the optionally substituted ring A is .

[00315] In some embodiments, the optionally substituted ring A is .

[00316] In some embodiments, the optionally substituted ring

Hey.

[00317] In some embodiments, the optionally substituted ring A is .

[00318] In some embodiments, the optionally substituted ring A is .

[00319] In some embodiments, the optionally substituted ring A is .

[00320] In some embodiments, the optionally substituted ring A is .

[00321] In some embodiments, the optionally substituted ring A is .

[00322] In some embodiments, the optionally substituted ring A is .

[00323] In some embodiments, the optionally substituted ring A is .

[00324] In some embodiments, the optionally substituted ring A is .

[00325] In some embodiments, the optionally substituted ring

Hey.

[00326] In some embodiments, the optionally substituted ring A is .

[00327] In some embodiments, the optionally substituted ring A is .

[00328] In some embodiments, the optionally substituted ring A is .

[00329] In some embodiments, the optionally substituted ring A is .

[00330] In some embodiments, the optionally substituted ring A is .

[00331] In some embodiments, the optionally substituted ring A is .

[00332] In some embodiments, the optionally substituted ring A is .

[00333] In some embodiments, the optionally substituted ring A is .

[00334] In some embodiments, the optionally substituted ring

N R1 A is R2 .

[00335] In some embodiments, the optionally substituted ring A is .

[00336] In some embodiments, the optionally substituted ring A is .

[00337] In some embodiments, the optionally substituted ring A is .

[00338] In some embodiments, the optionally substituted ring R1 R2 A is N .

[00339] In some embodiments, the optionally substituted ring R1 R2

No.

[00340] In some embodiments, the optionally substituted ring A is .

[00341] In some embodiments, the optionally substituted ring A is .

[00342] In some embodiments, the optionally substituted ring

Hey.

[00343] In some embodiments, the optionally substituted ring A is .

[00344] In some embodiments, the optionally substituted ring A is .

[00345] In some embodiments, the optionally substituted ring A is .

[00346] In some embodiments, the optionally substituted ring A is .

[00347] In some embodiments, the optionally substituted ring A is .

[00348] In some embodiments, the optionally substituted ring A is .

[00349] In some embodiments, the optionally substituted ring A is .

[00350] In some embodiments, the optionally substituted ring

Hey.

[00351] In some embodiments, the optionally substituted ring A is .

[00352] In some embodiments, the optionally substituted ring A is .

[00353] In some embodiments, the optionally substituted ring A is .

[00354] In some embodiments, the optionally substituted ring A is .

[00355] In some embodiments, the optionally substituted ring A is .

[00356] In some embodiments, the optionally substituted ring A is .

[00357] In some embodiments, the optionally substituted ring

Hey.

[00358] In some embodiments, the optionally substituted ring A is .

[00359] In some embodiments, the optionally substituted ring A is .

[00360] In some embodiments, the optionally substituted ring R1

No

No.

[00361] In some embodiments, the optionally substituted ring A is .

[00362] In some embodiments, the optionally substituted ring R2 R1

N R1 Ae N .

[00363] In some embodiments, the optionally substituted ring R1 R2

N R2 Ae N .

[00364] In some embodiments, the optionally substituted ring A is .

[00365] In some embodiments, the optionally substituted ring

Hey.

[00366] In some embodiments, the optionally substituted ring A is .

[00367] In some embodiments, the optionally substituted ring A is .

[00368] In some embodiments, the optionally substituted ring R2

N N R1 Ae N .

[00369] In some embodiments, the optionally substituted ring

N N R2

N A is R1 .

[00370] In some embodiments, the optionally substituted ring

N N R2 N A is R1 .

[00371] In some embodiments, the optionally substituted ring R1 R2

The Aé N.

[00372] In some embodiments, the optionally substituted ring R1 R2

N Aé O .

[00373] In some embodiments, the optionally substituted ring

R1 R2

S Aé N .

[00374] In some embodiments, the optionally substituted ring R1 R2

N Aé S .

[00375] In some embodiments, the substituted ring A is R2

S 1

R R2 .

[00376] In some embodiments, the substituted ring A is R1

S 2

R R1 .

[00377] In some embodiments, the substituted ring A is R2

The R1 R2 .

[00378] In some embodiments, the substituted ring A is R1

the 2

R R1 .

[00379] In some embodiments, the substituted ring A is R2

NH R1 R2 .

[00380] In some embodiments, the substituted ring A is

R2 R1

No. 1

R. R2 R1

No

[00381] In some embodiments, the substituted ring A is R1.

[00382] In some embodiments, the substituted ring A is R1

N 2

R R1 .

[00383] In some embodiments, the substituted ring A is R2 R1

No. 1

R R2 .

[00384] In some embodiments, the substituted ring A is R1

HN 2

R R1 .

[00385] In some embodiments, the substituted ring A is R2 R1

N R1 . R2 R1

No

[00386] In some embodiments, the substituted ring A is R1.

[00387] In some embodiments, the substituted ring A is R1 R2

N R2 .

[00388] In some embodiments, the substituted ring A is

R1

N R2 R1 .

[00389] In some embodiments, the substituted ring A is R2 R1

N R1 R2 .

[00390] In some embodiments, the optionally substituted ring R2

N N R1 A is R2 .

[00391] In some embodiments, the optionally substituted ring R2

N N R1 R1 Ae .

[00392] In some embodiments, the optionally substituted ring A is .

[00393] In some embodiments, the optionally substituted ring A is .

[00394] In some embodiments, the optionally substituted ring A is .

[00395] In some embodiments, the optionally substituted ring

Hey.

[00396] In some embodiments, the optionally substituted ring A is .

[00397] In some embodiments, the optionally substituted ring A is .

[00398] In some embodiments, the optionally substituted ring A is .

[00399] In some embodiments, the optionally substituted ring A is .

[00400] In some embodiments, the optionally substituted ring A is .

[00401] In some embodiments, the optionally substituted ring A is .

[00402] In some embodiments, the optionally substituted ring A is .

[00403] In some embodiments, the optionally substituted ring A is .

[00404] In some embodiments, the optionally substituted ring A is .

[00405] In some embodiments, the optionally substituted ring A is .

[00406] In some embodiments, the optionally substituted ring A is .

[00407] In some embodiments, the optionally substituted ring A is .

[00408] In some embodiments, the optionally substituted ring A is .

[00409] In some embodiments, the optionally substituted ring A is .

[00410] In some embodiments, the optionally substituted ring

R1 R2

N Ae R1 N .

[00411] In some embodiments, the optionally substituted ring A is .

[00412] In some embodiments, the optionally substituted ring A is .

[00413] In some embodiments, the optionally substituted ring R1 1 R R2

N Aé N .

[00414] In some embodiments, the optionally substituted ring A is .

[00415] In some embodiments, the optionally substituted ring A is .

[00416] In some embodiments, the optionally substituted ring A is .

[00417] In some embodiments, the optionally substituted ring

hey

[00418] In some embodiments, the optionally substituted ring A is selected from the group consisting of: , , , , , , , , , , , , , , , ,

AT THE N , , , , , , , , , , , ,

, , , , , , , , , , , , , , , , , , , , and .

[00419] In some embodiments, the optionally substituted ring A is selected from the group consisting of: , , , , , , , , ,

, , , , , , ,

AT THE

Huh .

[00420] In some embodiments, the optionally substituted ring A is selected from the group consisting of: , , , , , , , , , , , , , ,

, , and .

[00421] In some embodiments, the optionally substituted ring A is selected from the group consisting of: , , , , and .

[00422] In some embodiments, the optionally substituted ring A is selected from the group consisting of: , , , and .

[00423] In some embodiments, the optionally substituted ring A is selected from the following: ; ; ; ; ;

; ; ; ; ; ;and .

[00424] In some embodiments of the compound of Formula AA, when ring A is phenyl, then R1 and R2 are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy , C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO-C6-C10 aryl, CO(5-10 membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl , OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13 )NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3 to 7 membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 3- to 7-membered heterocycloalkyl are optional ally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 7 membered, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl , NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl; where each C1-C6 alkyl substituent and each substituent

C1-C6 alkoxy of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy, halo, NR8R9 or oxo; wherein 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring which includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with a or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl , OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein a C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl 3- to 10-membered yl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo , NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[00425] In some embodiments of the compound of Formula AA, when ring A is pyridyl, then R1 and R2 are each independently

selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl) , CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), C6-C10 aryl, 5 to 5 membered heteroaryl 10 membered, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(3 to 7 membered heterocycloalkyl), NHCOC2 -C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO( 3 to 7 membered), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(3 to 7 membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or the heterocyclic ring is optionally independently replaced by a or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1 -C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, in that C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl la with 3 to 10 members are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. The A' Ring when Formula AA is Formula AA-1

[00426] In some embodiments, A' is a 6- to 10-membered (e.g., 6-membered) heteroaryl or a C6-C10 (e.g., C6) monocyclic or bicyclic aryl, such as phenyl.

[00427] In some embodiments, A' is a 6- to 10-membered (e.g., 6-membered) heteroaryl or a C7-C10 (e.g., C6) monocyclic or bicyclic aryl.

[00428] In some embodiments, A' is a 6- to 10-membered heteroaryl (eg, 6-membered).

[00429] In some embodiments of the compound of Formula AA-1, A' is a C6-C10 aryl.

[00430] In some embodiments, A' is a 5-membered heteroaryl comprising 2 or more heteroatoms.

[00431] In some embodiments, A' is a 5-membered heteroaryl comprising 1 heteroatom and/or heteroatomic group selected from N, NH and NR1.

[00432] In some embodiments, A' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)= No.

[00433] In some embodiments, A' is a 5-membered heteroaryl containing a sulfur and optionally one or more nitrogens.

[00434] In some embodiments, A' is a C6-C10 aryl.

[00435] In some embodiments, A' is different from pyrazolyl.

[00436] In some embodiments, A' is thiophenyl (eg, thio-phen-3-yl).

[00437] In some embodiments, A' is thiazolyl (e.g., thiazol-2-yl or thiazol-3-yl).

[00438] In some embodiments, A' is pyrazolyl (eg, pyrazol-2-yl).

[00439] In some embodiments, A' is imidazolyl (eg imidazol-2-yl).

[00440] In some embodiments, A' is naphthyl.

[00441] In some embodiments, A' is furanyl.

[00442] In some embodiments, A' is pyridyl.

[00443] In some embodiments, A' is indazolyl.

[00444] In some embodiments, A' is phenyl, m is 0 or 1, and n is 0, 1 or 2.

[00445] In some embodiments, A' is furanyl, m is 0 or 1, and n is 0, 1 or 2.

[00446] In some embodiments, A' is thiophenyl, m is 0 or 1, and n is 0, 1 or 2.

[00447] In some embodiments, A' is thiazolyl, m is 0 or 1, and n is 0, 1 or 2.

[00448] In some embodiments, A' is pyrazolyl, m is 0 or 1, and n is 0, 1, or 2.

[00449] In some embodiments, A' is pyridyl, m is 0 or 1, and n is 0, 1, or 2.

[00450] In some embodiments, A' is indazolyl, m is 0 or 1, and n is 0, 1 or 2.

[00451] In some embodiments, A' is thiazolyl, m is 1, and n is 1.

[00452] In some embodiments, A' is pyrazolyl, m is 1 or 2, and n is 1 or 2.

[00453] In some embodiments, A' is imidazolyl, m is 1 or 2, and n is 1 or 2.

[00454] In some embodiments, A' is pyrrolyl, m is 1 or 2, and n is 1 or 2.

[00455] In some embodiments, A' is oxazolyl, m is 1, and n is 1.

[00456] In some embodiments, A' is furanyl, m is 1 or 2, and n is 1 or 2.

[00457] In some embodiments, A' is isoxazolyl, m is 1, and n is 1.

[00458] In some embodiments, A' is isothiazolyl, m is 1, and n is 1.

[00459] In some embodiments, A' is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl), m is 1, and n is 1.

[00460] In some embodiments, A' is pyridinyl, m is 1 or 2, and n is 1 or 2.

[00461] In some embodiments, A' is pyridimidinyl, m is 1 or 2, and n is 1 or 2.

[00462] In some embodiments, A' is pyrazinyl, m is 1 or 2, and n is 1 or 2.

[00463] In some embodiments, A' is pyridazinyl, m is 1 or 2, and n is 1 or 2.

[00464] In some embodiments, A' is triazinyl, m is 1, and n is 1.

[00465] In some embodiments, A' is one of the rings disclosed below optionally substituted as disclosed below, wherein, in each case, the bond that is shown to be broken by the wavy line connects A to the chemical moiety S(O)(NHR3) )=N of Formula AA.

[00466] In some embodiments, the optionally substituted ring A' ( ) is .

[00467] In some embodiments, the optionally substituted ring A' is .

[00468] In some embodiments, the optionally substituted ring A' is .

[00469] In some embodiments, the optionally substituted ring A' is .

[00470] In some embodiments, the optionally substituted ring A' is .

[00471] In some embodiments, the optionally substituted ring A' is .

[00472] In some embodiments, the optionally substituted ring A' is .

[00473] In some embodiments, the optionally substituted ring A' is .

[00474] In some embodiments, the optionally substituted ring A' is .

[00475] In some embodiments, the optionally substituted ring A' is .

[00476] In some embodiments, the optionally substituted ring A' is .

[00477] In some embodiments, the optionally substituted ring A' is .

[00478] In some embodiments, the optionally substituted ring R1

N A' is S .

[00479] In some embodiments, the optionally substituted ring

S R1 N A' is .

[00480] In some embodiments, the optionally substituted ring

A' is .

[00481] In some embodiments, the optionally substituted ring A' is .

[00482] In some embodiments, the optionally substituted ring A' is .

[00483] In some embodiments, the optionally substituted ring A' is .

[00484] In some embodiments, the optionally substituted ring

HN N R1 A' is R2 .

[00485] In some embodiments, the optionally substituted ring A' is .

[00486] In some embodiments, the optionally substituted ring A' is .

[00487] In some embodiments, the optionally substituted ring R2

N R1 A' is N.

[00488] In some embodiments, the optionally substituted ring R1 R2

N A' is N .

[00489] In some embodiments, the optionally substituted ring R1

NH R2 A' is N.

[00490] In some embodiments, the optionally substituted ring A' is .

[00491] In some embodiments, the optionally substituted ring A' is .

[00492] In some embodiments, the optionally substituted ring A' is .

[00493] In some embodiments, the optionally substituted ring A' is .

[00494] In some embodiments, the optionally substituted ring A' is .

[00495] In some embodiments, the optionally substituted ring R2

NH R1 A' is .

[00496] In some embodiments, the optionally substituted ring

R2 R1

N A' is .

[00497] In some embodiments, the optionally substituted ring

NH R1 A' is R2 .

[00498] In some embodiments, the substituted ring A' is

S 1

R R2 .

[00499] In some embodiments, the substituted ring A' is

The R1 R2 .

[00500] In some embodiments, the substituted ring A' is

HN 1

R R2 . R2 R1

No

[00501] In some embodiments, the substituted ring A' is .

[00502] In some embodiments, the substituted ring A' is R2

N R1 .

[00503] In some embodiments, the optionally substituted ring R2

N N R1 A' is N.

[00504] In some embodiments, the optionally substituted ring

N N R2

N A' is R1 .

[00505] In some embodiments, the optionally substituted ring

N N

R N 2 A' is R1 .

[00506] In some embodiments, the optionally substituted ring R1 R2

The A' is N.

[00507] In some embodiments, the optionally substituted ring R1 R2

N A' is O.

[00508] In some embodiments, the optionally substituted ring R1 R2

S A' is N .

[00509] In some embodiments, the optionally substituted ring R1 R2

N A' is S .

[00510] In some embodiments, the optionally substituted ring A' is .

[00511] In some embodiments, the optionally substituted ring A' is .

[00512] In some embodiments, the optionally substituted ring A' is .

[00513] In some embodiments, the optionally substituted ring

A' is.

[00514] In some embodiments, the optionally substituted ring A' is .

[00515] In some embodiments, the optionally substituted ring A' is .

[00516] In some embodiments, the optionally substituted ring A' is .

[00517] In some embodiments, the optionally substituted ring A' is .

[00518] In some embodiments, the optionally substituted ring A' is .

[00519] In some embodiments, the optionally substituted ring A' is .

[00520] In some embodiments, the optionally substituted ring A' is .

[00521] In some embodiments, the optionally substituted ring

A' is.

[00522] In some embodiments, the optionally substituted ring A' is .

[00523] In some embodiments, the optionally substituted ring A' is .

[00524] In some embodiments, the optionally substituted ring A' is .

[00525] In some embodiments, the optionally substituted ring R1 R2 A' is N.

[00526] In some embodiments, the optionally substituted ring R1 R2

N A' is .

[00527] In some embodiments, the optionally substituted ring A' is .

[00528] In some embodiments, the optionally substituted ring A' is .

[00529] In some embodiments, the optionally substituted ring

A' is.

[00530] In some embodiments, the optionally substituted ring A' is .

[00531] In some embodiments, the optionally substituted ring A' is .

[00532] In some embodiments, the optionally substituted ring A' is .

[00533] In some embodiments, the optionally substituted ring A' is .

[00534] In some embodiments, the optionally substituted ring A' is .

[00535] In some embodiments, the optionally substituted ring A' is .

[00536] In some embodiments, the optionally substituted ring A' is .

[00537] In some embodiments, the optionally substituted ring

A' is.

[00538] In some embodiments, the optionally substituted ring A' is .

[00539] In some embodiments, the optionally substituted ring A' is .

[00540] In some embodiments, the optionally substituted ring A' is .

[00541] In some embodiments, the optionally substituted ring A' is .

[00542] In some embodiments, the optionally substituted ring A' is .

[00543] In some embodiments, the optionally substituted ring A' is .

[00544] In some embodiments, the optionally substituted ring A' is .

[00545] In some embodiments, the optionally substituted ring

A' is.

[00546] In some embodiments, the optionally substituted ring A' is .

[00547] In some embodiments, the optionally substituted ring A' is .

[00548] In some embodiments, the optionally substituted ring A' is .

[00549] In some embodiments, the optionally substituted ring R1

No

N A' is .

[00550] In some embodiments, the optionally substituted ring A' is .

[00551] In some embodiments, the optionally substituted ring R2 R1

N R1 A' is N.

[00552] In some embodiments, the optionally substituted ring R1 R2

N 2

R A' is N .

[00553] In some embodiments, the substituted ring A' is R1

S R2 R1 .

[00554] In some embodiments, the substituted ring A' is R1

The R2 R1.

[00555] In some embodiments, the substituted ring A' is R2

NH 1

R R2 .

[00556] In some embodiments, the substituted ring A' is R2 R1

N R1 . R2 R1

No

[00557] In some embodiments, the substituted ring A' is R1 .

[00558] In some embodiments, the substituted ring A' is R1

N R2 R1 .

[00559] In some embodiments, the substituted ring A' is R2 R1

No. 1

R R2 .

[00560] In some embodiments, the substituted ring A' is

R1

HN 2

R R1 .

[00561] In some embodiments, the substituted ring A' is R2 R1

N R1 . R2 R1

No

[00562] In some embodiments, the substituted ring A' is R1.

[00563] In some embodiments, the substituted ring A' is R1 R2

N R2 .

[00564] In some embodiments, the substituted ring A' is R1

N R2 R1 .

[00565] In some embodiments, the substituted ring A' is R2 R1

N R1 R2 .

[00566] In some embodiments, the optionally substituted ring R2

N N R1 A' is R2 .

[00567] In some embodiments, the optionally substituted ring

R2

N N R1 R1 A' is .

[00568] In some embodiments, the optionally substituted ring A' is .

[00569] In some embodiments, the optionally substituted ring A' is .

[00570] In some embodiments, the optionally substituted ring A' is .

[00571] In some embodiments, the optionally substituted ring A' is .

[00572] In some embodiments, the optionally substituted ring A' is .

[00573] In some embodiments, the optionally substituted ring A' is .

[00574] In some embodiments, the optionally substituted ring

A' is.

[00575] In some embodiments, the optionally substituted ring A' is .

[00576] In some embodiments, the optionally substituted ring A' is .

[00577] In some embodiments, the optionally substituted ring A' is .

[00578] In some embodiments, the optionally substituted ring A' is .

[00579] In some embodiments, the optionally substituted ring A' is .

[00580] In some embodiments, the optionally substituted ring A' is .

[00581] In some embodiments, the optionally substituted ring

A' is.

[00582] In some embodiments, the optionally substituted ring A' is .

[00583] In some embodiments, the optionally substituted ring A' is .

[00584] In some embodiments, the optionally substituted ring A' is .

[00585] In some embodiments, the optionally substituted ring A' is .

[00586] In some embodiments, the optionally substituted ring R1 R2

N A' is R1 N .

[00587] In some embodiments, the optionally substituted ring A' is .

[00588] In some embodiments, the optionally substituted ring

A' is.

[00589] In some embodiments, the optionally substituted ring R1 R1 R2

N A' is N .

[00590] In some embodiments, the optionally substituted ring A' is .

[00591] In some embodiments, the optionally substituted ring A' is selected from the group consisting of: , , , , , , , , , , , , , , , ,

AT THE

Huh .

[00592] In some embodiments, the optionally substituted ring

A' is selected from the group consisting of: , , , , , , , , , , , , , , , ,

AT THE

Huh .

[00593] In some embodiments, the optionally substituted ring A' is selected from the group consisting of: , , , , , , , ,

, , , , , , , , and .

[00594] In some embodiments, the optionally substituted ring A' is selected from the group consisting of: , , , , and .

[00595] In some embodiments, the optionally substituted ring A' is selected from the group consisting of: , and .

[00596] In some embodiments, the optionally substituted ring

A' is selected from the following: ; ; ; ; ; ;and .

[00597] In some embodiments of the compound of Formula AA-1, when ring A' is phenyl, then R1 and R2 are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1 -C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2 -C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N( C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-( C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and heterocycloalkyl with 3 to 7-membered, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 3- to 7-membered heterocycloalkyl are the optionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 7 membered, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl , NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl),

NHCO(3- to 7-membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring which includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with a or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl , OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein a C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl 3- to 10-membered yl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo , NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[00598] In some embodiments of the compound of Formula AA-1, when ring A is pyridyl, then R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6- C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2 , NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1- C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted ionized by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 to 5 membered, 5 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO( 5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl, the 5-10-membered heteroaryl, the NHCOC6-C10 aryl,

NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or the heterocyclic ring is optionally independently replaced by a or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1 -C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, in that C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl la with 3 to 10 members are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. The A'' Ring when Formula AA is Formula AA-2

[00599] In some embodiments, A'' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)= No.

[00600] In some embodiments, A'' is thiophen-2-yl.

[00601] In some embodiments, A'' is furan-2-ila.

[00602] In some embodiments, A'' is one of the rings disclosed below optionally substituted as disclosed below, wherein, in each case, the bond that is shown to be broken by the wavy line connects A to the chemical moiety S(O)( NHR3)=N of Formula AA.

[00603] In some embodiments, the optionally substituted ring A'' ( ) is .

[00604] In some embodiments, the optionally substituted ring A'' is .

[00605] In some embodiments, the optionally substituted ring A'' is .

[00606] In some embodiments, the optionally substituted ring

S A'' is R1.

[00607] In some embodiments, the optionally substituted ring A'' is .

[00608] In some embodiments, the optionally substituted ring A'' is .

[00609] In some embodiments, the optionally substituted ring R1

The A'' is .

[00610] In some embodiments, the optionally substituted ring

The A'' is R1.

[00611] In some embodiments, the optionally substituted ring A'' is . The A'' Ring when Formula AA is Formula AA-3

[00612] In some embodiments, A'' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)= No.

[00613] In some embodiments, A'' is thiophen-2-yl.

[00614] In some embodiments, A'' is furan-2-ila.

[00615] In some embodiments, A'' is furan-2-yl replaced by 2 R1'.

[00616] In some embodiments, A'' is furan-2-yl replaced by 2 R2'.

[00617] In some embodiments, A'' is furan-2-yl substituted with 1 R1' and substituted with 1 R2'.

[00618] In some embodiments, A'' is thiophen-2-yl substituted by 2 R1'.

[00619] In some embodiments, A'' is thiophen-2-yl substituted by 2 R2'.

[00620] In some embodiments, A'' is thiophen-2-yl substituted with 1 R1' and substituted with 1 R2'.

[00621] In some embodiments, A'' is one of the rings disclosed below optionally substituted as disclosed below, wherein, in each case, the bond that is shown to be broken by the wavy line connects A'' to the chemical moiety S(O) )(NHR3)=N of Form

mule AA.

[00622] In some embodiments, the optionally substituted ring R2'

S 1' A( ) is R .

[00623] In some embodiments, the optionally substituted ring A'' is .

[00624] In some embodiments, the optionally substituted ring A'' is .

[00625] In some embodiments, the optionally substituted ring A'' is .

[00626] In some embodiments, the optionally substituted ring A'' is .

[00627] In some embodiments, the optionally substituted ring R2'

S R 1' A'' is .

[00628] In some embodiments, the optionally substituted ring A'' is .

[00629] In some embodiments, the optionally substituted ring

A is selected from the group consisting of: and .

[00630] In some embodiments, the optionally substituted ring A is . The A'' Ring when the compound is a compound of Formula AA-4

[00631] In some embodiments, A'' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)= No.

[00632] In some embodiments, A'' is thiophen-2-yl.

[00633] In some embodiments, A'' is furan-2-ila.

[00634] In some embodiments, A'' is one of the rings disclosed below optionally substituted as disclosed below, wherein, in each case, the bond that is shown to be broken by the wavy line connects A to the chemical moiety S(O)( NHR3)=N of Formula AA.

[00635] In some embodiments, the optionally substituted ring R2''

S 1 A( ) is R .

[00636] In some embodiments, the optionally substituted ring A'' is .

[00637] In some embodiments, the optionally substituted ring A'' is .

[00638] In some embodiments, the optionally substituted ring A'' is .

[00639] In some embodiments, the optionally substituted ring A'' is .

[00640] In some embodiments, the optionally substituted ring A'' is .

[00641] In some embodiments, the optionally substituted ring

oh

S A'' is F.

[00642] In some embodiments, the optionally substituted ring H3C

S A'' is HO .

[00643] In some embodiments, the optionally substituted ring A'' is .

[00644] In some embodiments, the optionally substituted ring A'' is .

The Ring when Formula AA is Formula AA-5

[00645] In some embodiments, it is .

[00646] In some embodiments, it is . R2''

S 1

[00647] In some embodiments, isR .

oh s

[00648] In some embodiments, it is F. H3C

s

[00649] In some embodiments, it is HO .

[00650] In some embodiments, it is .

[00651] In some embodiments, it is . Groups R1, R1', R2, R2' and R2'' Groups R1 and R2

[00652] In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo , C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00653] In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo, or NR8R9.

[00654] In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00655] In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl;

pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00656] In some embodiments, R1, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl. For example, R1 is fluoro.

[00657] In some embodiments, R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (for example, R1 is 2-hydroxy-2-propyl; or R1 is 1,2-dihydroxy-2 -propyl).

[00658] In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo , C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00659] In some embodiments, R2, when present, is independent

selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo or NR8R9.

[00660] In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00661] In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00662] In some embodiments, R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.

[00663] In some embodiments, R2, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro.

[00664] In some embodiments, one or more R1 when present is independently the C1-C6 alkyl substituted by one or more hydroxy.

[00665] In certain of these embodiments, one or more R1 is independent.

carefully selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.

[00666] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (e.g., one) NR8R9.

[00667] In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.

[00668] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (eg, one) R15.

[00669] In certain such embodiments (e.g., a2 = 1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

[00670] In certain of these embodiments (e.g. a2 = 1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2- hydroxy-2-propyl.

[00671] In certain embodiments (eg a2 = 1), one or more R1 is independently selected from: , and .

[00672] In certain embodiments (eg a2 > 1), one or more R1 is .

[00673] In some embodiments, one or more R1 is independently C1-C6 alkyl substituted by one or more (e.g., one) NR8R9 and further optionally substituted by one or more halo.

[00674] In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroethyl-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroethyl-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroethyl-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroethyl-1-yl; 1-dimethylamino-2,2,2-trifluoroethyl-1-yl; 1-dimethylamino-2,2,2-trimethylethyl-1-yl; and dimethylamino(cyclopropyl)methyl (for example, one or more R1 is dimethylaminomethyl or methylaminomethyl).

[00675] In some embodiments, one or more R1 is C1-C6 alkyl which is optionally substituted by one or more halo. In certain such embodiments, one or more R1 is C2 -C6 alkyl which is optionally substituted by one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.

[00676] In some embodiments, one or more R1, when present, is 3- to 7-membered heterocycloalkyl optionally substituted by one or more oxo and further optionally substituted by one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.

[00677] In certain of any of these foregoing embodiments of R1, one or more R2 are independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more plus C1-C6 alkoxy, and halo.

[00678] In some embodiments, R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring (e.g., C5 or C6 carbocyclic ring ) or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or the heterocyclic ring is optionally substituted independently with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g. methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g. isopropoxy ), OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, heterocycloalkyl 3- to 10-membered (e.g., azetidinyl or oxetanyl) and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the heteroaryl with 5 to 10 members The C3-C10 cycloalkyl and the 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo (e.g. fluoro), C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g. amino, methylamino or dimethylamino), =NR10, CO-OC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[00679] In some embodiments, R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a C5-C6 carbocyclic ring mo-

nocyclic or bicyclic optionally independently substituted with one or more substituents, each independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino and dimethylamino; or R1 and R2 are on adjacent atoms and, taken together, independently form , , or , each of which is optionally substituted by one or more substituents independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino and dimethylamino; wherein the asterisk represents a point of attachment to a carbon atom; and o represents a point of attachment to a carbon or a nitrogen atom.

[00680] In some embodiments, R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic spirocyclic carbocyclic ring, in which the carbocyclic ring is optional - finally substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino and dimethylamino.

[00681] In some embodiments, R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O) two; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and/or R2), wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents, each independently selected from hydroxy , fluoro, amino, methylamino and dimethylamino.

[00682] In some embodiments, R1 and R2 are different.

[00683] In some embodiments, R1 and R2 are the same.

[00684] In some embodiments, R1 is para or meta with respect to R2.

[00685] In some embodiments, R1 is para or ortho to R2.

[00686] In some embodiments, R1 is ortho or meta to R2.

[00687] In some embodiments, R1 is para with respect to R2.

[00688] In some embodiments, R1 is meta relative to R2.

[00689] In some embodiments, R1 is ortho to R2. The R1 and R2 Groups when Formula AA is Formula AA-1

[00690] In some embodiments, R1, when present, is independent

preferably selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00691] In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo, or NR8R9.

[00692] In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00693] In some embodiments, R1, when present, is selected

none from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00694] In some embodiments, R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (for example, R1 is 2-hydroxy-2-propyl; or R1 is 1,2-dihydroxy-2 -propyl).

[00695] In some embodiments, R1, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl. For example, R1 is fluoro.

[00696] In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo , C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 al-

kilo; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00697] In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo, or NR8R9.

[00698] In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00699] In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00700] In some embodiments, R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.

[00701] In some embodiments of the compound of Formula AA-1,

R2, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro.

[00702] In some embodiments, one or more R1 when present is independently the C1-C6 alkyl substituted by one or more hydroxy.

[00703] In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.

[00704] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (eg, one) NR8R9.

[00705] In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.

[00706] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (eg, one) R15.

[00707] In certain such embodiments (e.g., a2 = 1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

[00708] In certain such embodiments (e.g. a2 = 1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2- hydroxy-2-propyl.

[00709] In certain embodiments (e.g. a2 = 1), one or more R1 is independently selected from:

, and .

[00710] In certain embodiments (eg a2 > 1), one or more R1 is .

[00711] In some embodiments, one or more R1 is independently C1-C6 alkyl substituted by one or more (eg, one) NR8R9 and further optionally substituted by one or more halo.

[00712] In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroethyl-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroethyl-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroethyl-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroethyl-1-yl; 1-dimethylamino-2,2,2-trifluoroethyl-1-yl; 1-dimethylamino-2,2,2-trimethylethyl-1-yl; and dimethylamino(cyclopropyl)methyl (for example, one or more R1 is dimethylaminomethyl or methylaminomethyl).

[00713] In some embodiments, one or more R1 is C1-C6 alkyl which is optionally substituted by one or more halo. In certain such embodiments, one or more R1 is C2 -C6 alkyl which is optionally substituted by one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.

[00714] In some embodiments, one or more R1, when present, is 3- to 7-membered heterocycloalkyl optionally substituted by one or more oxo and further optionally substituted by one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.

[00715] In certain of any of these foregoing embodiments of R1, one or more R2 are independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more plus C1-C6 alkoxy, and halo.

[00716] In some embodiments of the compound of Formula AA-1, R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring (e.g. C5 ring or C6 carbocyclic) or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or the heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g. methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g. isopropoxy), OC3- C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl ( for example, azetidinyl or oxetanyl) and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, The C3-C10 cycloalkyl and heterocycloalkyl with 3 to 10 mem-

Bros are optionally substituted by one or more substituents each independently selected from hydroxy, halo (e.g. fluoro), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g. amino, methylamino or dimethylamino), =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[00717] In some embodiments of the compound of Formula AA-1, R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C5-C6 carbocyclic ring optionally independently substituted by one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein the methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino and dimethylamino; or

[00718] R1 and R2 are on adjacent atoms and, taken together, independently form , , or , where each is optionally substituted by one or more substituents independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino and dimethylamino; wherein the asterisk represents a point of attachment to a carbon atom; and o represents a point of attachment to a carbon or a nitrogen atom.

[00719] In some embodiments of the compound of Formula AA-1, R1 and R2 are on adjacent atoms and, considered together with the atoms connecting them, independently form at least one bicyclic spirocyclic spirocyclic carbocyclic ring, in which the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino and dimethylamino.

[00720] In some embodiments of the compound of Formula AA-1, R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to 12-membered heterocyclic ring. cyclic, wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and/or R2), wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents, each one independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein the methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluoro, amino , methylamino and dimethylamino. The R1 and R2 Groups when Formula AA is Formula AA-2

[00721] In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo , C1-C6 alkoxy or NR8R9;

C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00722] In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo, or NR8R9.

[00723] In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00724] In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;

1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00725] In some embodiments, R1, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl. For example, R1 is fluoro.

[00726] In some embodiments, R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro. For example, R1, when present, is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (for example, R1 is 2-hydroxy-2-propyl; or R1 is 1,2 -dihydroxy-2-propyl).

[00727] In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo , C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2;

NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00728] In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo, or NR8R9.

[00729] In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00730] In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00731] In some embodiments, R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.

[00732] In some embodiments, R2, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro.

[00733] In some embodiments, one or more R1 when present is independently the C1-C6 alkyl substituted by one or more hydroxy.

[00734] In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.

[00735] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (e.g., one) NR8R9.

[00736] In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.

[00737] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (eg, one) R15.

[00738] In certain such embodiments (e.g., a2 = 1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

[00739] In certain such embodiments (e.g., a2 = 1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2- hydroxy-2-propyl.

[00740] In certain embodiments (eg a2 = 1), one or more R1 is independently selected from: , and .

[00741] In certain embodiments (eg a2 > 1), one or more R1 is .

[00742] In some embodiments, one or more R1 is independently C1-C6 alkyl substituted by one or more (eg, one) NR8R9 and further optionally substituted by one or more halo.

[00743] In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroethyl-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroethyl-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroethyl-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroethyl-1-yl; 1-dimethylamino-2,2,2-trifluoroethyl-1-yl; 1-dimethylamino-2,2,2-trimethylethyl-1-yl; and dimethylamino(cyclopropyl)methyl (for example, one or more R1 is dimethylaminomethyl or methylaminomethyl).

[00744] In some embodiments, one or more R1 is C1-C6 alkyl which is optionally substituted by one or more halo. In certain such embodiments, one or more R1 is C2 -C6 alkyl which is optionally substituted by one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.

[00745] In some embodiments, one or more R1, when present, is 3- to 7-membered heterocycloalkyl optionally substituted by one or more oxo and further optionally substituted by one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.

[00746] In certain of any of these foregoing embodiments of R1, one or more R2 are independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more plus C1-C6 alkoxy, and halo.

[00747] In some embodiments, a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic 5- to 12-membered heterocyclic ring or bicyclic that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, when the compound of Formula AA is a compound of Formula AA-2 , and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy , OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C 6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. Groups R1' and R2' when Formula AA is Formula AA-3

[00748] In some embodiments, R1', when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted by one or more hydroxy, C2-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; Cl; BR; I; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00749] In some embodiments, R1', when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted by one or more hydroxyl or NR8R9.

[00750] In some embodiments, R1', when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl 1,2-dihydroxy-2-propyl; isopropyl; ethyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12. In certain such embodiments, R1' is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. For example, R1' is 2-hydroxy-2-propyl. As another example, R1' is 1,2-dihydroxy-2-propyl.

[00751] In some embodiments, R1', when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; isopropyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chlorine;

phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12. For example, R1' is 2-hydroxy-2-propyl.

[00752] In some embodiments, R2', when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted by one or more hydroxy, C2-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; Cl; BR; I; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00753] In some embodiments, R2', when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted by one or more hydroxyl, halo, or NR8R9.

[00754] In some embodiments, R2', when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl 1,2-dihydroxy-2-propyl; isopropyl; ethyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-

(dimethylamino)ethyl; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12. For example, R2' is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (for example, R2' is 2-hydroxy-2-propyl; or R2' is 1,2-di- hydroxy-2-propyl).

[00755] In some embodiments, R2', when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; isopropyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12. For example, R2' is 2-hydroxy-2-propyl.

[00756] In some embodiments, one or more R1' when present is independently the C2-C6 alkyl substituted by one or more hydroxy.

[00757] In certain of these embodiments, one or more R1' is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.

[00758] In some embodiments, one or more R1', when present, is independently a C2-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (e.g., one) NR8R9.

[00759] In certain such embodiments, one or more R1' is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.

[00760] In some embodiments, one or more R1', when present, is independently a C2-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (eg, one) R15.

[00761] In certain of these modes (eg a2 = 1 or 2),

one or more R1' is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

[00762] In certain of these embodiments (e.g. a2 = 1), one or more R1' is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2 -hydroxy-2-propyl.

[00763] In certain embodiments (eg a2 = 1), one or more R1' is independently selected from: , and .

[00764] In certain embodiments (eg a2 > 1), one or more R1' is .

[00765] In some embodiments, one or more R1' is independently C2-C6 alkyl substituted by one or more (e.g., one) NR8R9 and further optionally substituted by one or more halo.

[00766] In certain of these embodiments, one or more R1' is independently selected from: 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (1-(cyclobutyl)amino-eth-1-yl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroethyl-1-yl; 1-dimethylamino-2,2, 2-trifluoroethyl-1-yl and 1-dimethylamino-2,2,2-trimethylethyl-1-yl.

[00767] In some embodiments, one or more R1' is C2-C6 alkyl which is optionally substituted by one or more halo. In certain such embodiments, one or more R1' is C2 -C6 alkyl which is optionally substituted by one or more halo. As non-limiting examples, R1' is ethyl or difluoroethyl.

[00768] In some embodiments, one or more R1', when present, is 3- to 7-membered heterocycloalkyl optionally substituted by one or more oxo and further optionally substituted by one or more C1-C6 alkyl. For example, R1' is 5-methyl-oxazolidin-2-one-5-yl.

[00769] In certain of any of the foregoing embodiments of R1', one or more R2' are independently selected from C2-C6 alkyl, C2-C6 alkyl optionally substituted by one or more hydroxy, C2-C6 alkyl optionally substituted by one or more plus C1-C6 alkoxy, Br, Cl and I.

[00770] In some embodiments, a pair of R1' and R2' on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C12 monocyclic or bicyclic carbocyclic ring or a heterocyclic ring with 5 to 12 monocyclic or bicyclic members that include from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C10 cycloalkyl, 3 to 10 membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloal 3- to 10-membered alkyl and heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy , oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[00771] In some embodiments, R1' and R2' are the same.

[00772] In some embodiments, R1' and R2' are different.

[00773] In some embodiments, R1' is meta relative to R2'.

[00774] In some embodiments, R1' is ortho to R2'.

R1 and R2'' when Formula AA is Formula AA-4

[00775] In some embodiments, R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

[00776] In some embodiments, R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo, or NR8R9.

[00777] In some embodiments, R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00778] In some embodiments, R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00779] In certain embodiments, R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (methylamino)methyl; (dimethylamino)methyl; and fluoro. As a non-limiting example of the foregoing embodiments, R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (for example, R1 is 2-hydroxy-2-propyl; or R1 is 1,2 -dihydroxy-2-propyl).

[00780] In some embodiments, R1 is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. In some embodiments of the compound of Formula AA-4, R1 is 2-hydroxy-2-propyl. In some embodiments of the compound of Formula AA-4, R1 is fluoro.

[00781] In some embodiments, R2'' is fluoro.

[00782] In some embodiments, R2'' is methyl.

[00783] In some embodiments, one or more R1 when present is independently the C1-C6 alkyl substituted by one or more hydroxy.

[00784] In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.

[00785] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (e.g., one) NR8R9.

[00786] In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.

[00787] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (eg, one) R15.

[00788] In certain such embodiments (e.g., a2 = 1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

[00789] In certain of these embodiments (e.g. a2 = 1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2- hydroxy-2-propyl.

[00790] In certain embodiments (eg a2 = 1), one or more R1 is independently selected from: , and .

[00791] In certain embodiments (eg a2 > 1), one or more R1 is .

[00792] In some embodiments, one or more R1 is independently C1-C6 alkyl substituted by one or more (eg, one) NR8R9 and further optionally substituted by one or more halo.

[00793] In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroethyl-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroethyl-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-

(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroethyl-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroethyl-1-yl; 1-dimethylamino-2,2,2-trifluoroethyl-1-yl; 1-dimethylamino-2,2,2-trimethylethyl-1-yl; and dimethylamino(cyclopropyl)methyl (for example, one or more R1 is dimethylaminomethyl or methylaminomethyl).

[00794] In some embodiments, one or more R1 is C1-C6 alkyl which is optionally substituted by one or more halo. In certain such embodiments, one or more R1 is C2 -C6 alkyl which is optionally substituted by one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.

[00795] In some embodiments, one or more R1, when present, is 3- to 7-membered heterocycloalkyl optionally substituted by one or more oxo and further optionally substituted by one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.

[00796] In some embodiments, a pair of R1 and R2'' on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C12 monocyclic or bicyclic carbocyclic ring or a heterocyclic ring with 5 to 12 monocyclic or bicyclic members that include from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN , COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9 , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl 3- to 10-membered yl and heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy , oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[00797] In some embodiments, R1 and R2'' are the same.

[00798] In some embodiments, R1 and R2'' are different.

[00799] In some embodiments, R1 is meta in relation to R2''.

[00800] In some embodiments, R1 is ortho to R2''. R1 and R2'' when Formula AA is Formula AA-5

[00801] In some embodiments, R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-

C6 alkyl.

[00802] In some embodiments, R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo, or NR8R9.

[00803] In some embodiments, R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00804] In some embodiments, R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.

[00805] In some embodiments, R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (for example, R1 is 2-hydroxy-2-propyl; or R1 is 1,2-dihydroxy-2 -propyl).

[00806] In some embodiments, R1 is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl. For example, R1 is fluoro.

[00807] In some embodiments, one or more R1 when present is independently the C1-C6 alkyl substituted by one or more hydroxy.

[00808] In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.

[00809] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (eg, one) NR8R9.

[00810] In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.

[00811] In some embodiments, one or more R1, when present, is independently a C1-C6 alkyl substituted by one or more hydroxy and further substituted by one or more (eg, one) R15.

[00812] In certain such embodiments (e.g., a2 = 1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

[00813] In certain such embodiments (e.g. a2 = 1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2- hydroxy-2-propyl.

[00814] In certain embodiments (eg a2 = 1), one or more R1 is independently selected from: , and .

[00815] In certain embodiments (e.g. a2 > 1), one or more

R1 is .

[00816] In some embodiments, one or more R1 is independently C1-C6 alkyl substituted by one or more (e.g., one) NR8R9 and further optionally substituted by one or more halo.

[00817] In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroethyl-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroethyl-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroethyl-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroethyl-1-yl; 1-dimethylamino-2,2,2-trifluoroethyl-1-yl; 1-dimethylamino-2,2,2-trimethylethyl-1-yl; and dimethylamino(cyclopropyl)methyl (for example, one or more R1 is dimethylaminomethyl or methylaminomethyl).

[00818] In some embodiments, one or more R1 is C1-C6 alkyl which is optionally substituted by one or more halo. In certain such embodiments, one or more R1 is C2 -C6 alkyl which is optionally substituted by one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.

[00819] In some embodiments, one or more R1, when present, is 3- to 7-membered heterocycloalkyl optionally substituted by one or more oxo and further optionally substituted by one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.

[00820] In certain of any of these foregoing embodiments of R1, one or more R2 are independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more plus C1-C6 alkoxy, and halo.

[00821] In some embodiments, R2'' is fluoro.

[00822] In some embodiments, R2'' is methyl. The variables o and p

[00823] In some embodiments, o=1 or 2.

[00824] In some embodiments, o=1.

[00825] In some embodiments, o=2.

[00826] In some modalities, p=0, 1, 2 or 3.

[00827] In some modalities, p=0.

[00828] In some modalities, p=1.

[00829] In some modalities, p=2.

[00830] In some modalities, o=1 and p=0.

[00831] In some modalities, o=2 and p=0.

[00832] In some modalities, o=1 and p=1.

[00833] In some modalities, o=1 and p=2.

[00834] In some modalities, o=2 and p=1.

[00835] In some modalities, o=2 and p=2.

[00836] In some modalities, o=2 and p=3. The B ring and substitutions in the B ring

[00837] In some embodiments, B is pyridyl or an N-oxide thereof (e.g., 2-pyridyl or an N-oxide thereof, 3-pyridyl or an N-oxide thereof, or 4-pyridyl or an N- oxide thereof).

[00838] In some embodiments, B is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl).

[00839] In some embodiments, B is a pyridyl N-oxide (e.g., 2-pyridyl N-oxide, 3-pyridyl N-oxide or 4-pyridyl N-oxide).

[00840] In some embodiments, B is pyrimidinyl or an N-oxide thereof (for example, 4-pyrimidinyl or an N-oxide thereof or 5-pyrimidinyl or an N-oxide thereof).

[00841] In some embodiments, B is pyridazinyl.

[00842] In some embodiments, B is pyrazinyl.

[00843] In some embodiments, B is triazinyl.

[00844] In some embodiments, B is one of the rings disclosed hereinafter, substituted as hereinafter disclosed, wherein, in each case, the bond which is shown to be broken by the wavy line connects B to the NHC(O) group of Formula AA.

[00845] In some embodiments, the substituted ring B is .

[00846] In some embodiments, the substituted ring B is .

[00847] In some embodiments, the substituted ring B is .

[00848] In some embodiments, the substituted ring B is .

[00849] In some embodiments, the substituted ring B is .

[00850] In some embodiments, the substituted ring B is

.

[00851] In some embodiments, the substituted ring B is .

[00852] In some embodiments, the substituted ring B is .

[00853] In some embodiments, the substituted ring B is .

[00854] In some embodiments, the substituted ring B is .

[00855] In some embodiments, the substituted ring B is R7 R7

N R6 .

[00856] In some embodiments, the substituted ring B is .

[00857] In some embodiments, the substituted ring B is .

[00858] In some embodiments, the substituted ring B is .

[00859] In some embodiments, the substituted ring B is .

[00860] In some embodiments, the substituted ring B is .

[00861] In some embodiments, the substituted ring B is .

[00862] In some embodiments, the substituted ring B is .

[00863] In some embodiments, the substituted ring B is .

[00864] In some embodiments, the substituted ring B is .

[00865] In some embodiments, the substituted ring B is .

[00866] In some embodiments, the substituted ring B is .

[00867] In some embodiments, the substituted ring B is .

[00868] In some embodiments, the substituted ring B is .

[00869] In some embodiments, the substituted ring B is .

[00870] In some embodiments, the substituted ring B is

.

[00871] In some embodiments, the substituted ring B is .

[00872] In some embodiments, the substituted ring B is .

[00873] In some embodiments, the substituted ring B is .

[00874] In some embodiments, the substituted ring B is .

[00875] In some embodiments, the substituted ring B is .

[00876] In some embodiments, the substituted ring B is .

[00877] In some embodiments, the substituted ring B is .

[00878] In some embodiments, the substituted ring B is .

[00879] In some embodiments, the substituted ring B is .

[00880] In some embodiments, the substituted ring B is .

[00881] In some embodiments, the substituted ring B is .

[00882] In some embodiments, the substituted ring B is .

[00883] In some embodiments, the substituted ring B is .

[00884] In some embodiments, the substituted ring B is

.

[00885] In some embodiments, the substituted ring B is .

[00886] In some embodiments, the substituted ring B is .

[00887] In some embodiments, the substituted ring B is .

[00888] In some embodiments, the substituted ring B is .

[00889] In some embodiments, the substituted ring B is .

[00890] In some embodiments, the substituted ring B is .

[00891] In some embodiments, the substituted ring B is

.

[00892] In some embodiments, the substituted ring B is .

[00893] In some embodiments, the substituted ring B is .

[00894] In some embodiments, the substituted ring B is .

[00895] In some embodiments, the substituted ring B is .

[00896] In some embodiments, the substituted ring B is .

[00897] In some embodiments, the substituted ring B is

.

[00898] In some embodiments, the substituted ring B is .

[00899] In some embodiments, the substituted ring B is .

[00900] In some embodiments, the substituted ring B is .

No

[00901] In some embodiments, the substituted ring B is .

[00902] In some embodiments, the substituted ring B is

No.

[00903] In some embodiments, the substituted ring B is

No.

[00904] In some embodiments, the substituted ring B is

No.

[00905] In some embodiments, the substituted ring B is

No.

[00906] In some embodiments, the substituted ring B is

No.

[00907] In some embodiments, the substituted ring B is

No.

[00908] In some embodiments, the substituted ring B is

No.

[00909] In some embodiments, the substituted ring B is

No.

[00910] In some embodiments, the substituted ring B is

No. No

[00911] In some embodiments, the substituted ring B is .

No

[00912] In some embodiments, the substituted ring B is .

[00913] In some embodiments, the substituted ring B is

No.

[00914] In some embodiments, the substituted ring B is R6 R7

No. R6

No

[00915] In some embodiments, the substituted ring B is .

[00916] In some embodiments, the substituted ring B is R6

No.

[00917] In some embodiments, the substituted ring B is

No.

[00918] In some embodiments, the substituted ring B is

F No.

[00919] In some embodiments, the substituted ring B is

No.

[00920] In some embodiments, the substituted ring B is

F No.

[00921] In some embodiments, the substituted ring B is

N F .

[00922] In some embodiments, the substituted ring B is selected from the group consisting of: , ,

, , , , , CF 3 CF3 CF3

N N N , , , , , N N N N N , , , , ,

N N e .

[00923] In some embodiments, the substituted ring B is selected from the group consisting of: , , and (eg, , and ).

[00924] In some embodiments, the substituted ring B is selected from the group consisting of: , , CF 3 CF3 CF3

N N N , , , , , N N N N N , , , , ,

N N e .

[00925] In some embodiments, the substituted ring B is selected from the group consisting of: , , , , , , ,

CF3

N N N , , , , ,

N N N N , , and .

[00926] In some embodiments, the substituted ring B is: R6 R6 R7 N O R7 .

[00927] In certain of these embodiments, the substituted ring B is: .

[00928] In some embodiments, the substituted ring B is .

[00929] In certain of these embodiments, the substituted ring B is .

[00930] In some embodiments, the substituted ring B is .

[00931] In certain of these embodiments, the substituted ring B is

. The B Ring when Formula AA is Formula AA-1

[00932] In some embodiments, B is pyridyl or an N-oxide thereof (e.g., 2-pyridyl or an N-oxide thereof, 3-pyridyl or an N-oxide thereof, or 4-pyridyl or an N- oxide thereof).

[00933] In some embodiments, B is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl).

[00934] In some embodiments, B is a pyridyl N-oxide (e.g., 2-pyridyl N-oxide, 3-pyridyl N-oxide or 4-pyridyl N-oxide).

[00935] In some embodiments, B is pyrimidinyl or an N-oxide thereof (for example, 4-pyrimidinyl or an N-oxide thereof or 5-pyrimidinyl or an N-oxide thereof).

[00936] In some embodiments, B is pyridazinyl.

[00937] In some embodiments, B is pyrazinyl.

[00938] In some embodiments, B is triazinyl.

[00939] In some embodiments, the substituted ring B is .

[00940] In some embodiments, the substituted ring B is .

[00941] In some embodiments, the substituted ring B is .

[00942] In some embodiments, the substituted ring B is

.

[00943] In some embodiments, the substituted ring B is .

[00944] In some embodiments, the substituted ring B is .

[00945] In some embodiments, the substituted ring B is .

[00946] In some embodiments, the substituted ring B is .

[00947] In some embodiments, the substituted ring B is .

[00948] In some embodiments, the substituted ring B is .

[00949] In some embodiments, the substituted ring B is

R7 R7

N R6''.

[00950] In some embodiments, the substituted ring B is .

[00951] In some embodiments, the substituted ring B is

[00952] In some embodiments, the substituted ring B is .

[00953] In some embodiments, the substituted ring B is .

[00954] In some embodiments, the substituted ring B is .

[00955] In some embodiments, the substituted ring B is .

[00956] In some embodiments, the substituted ring B is

.

[00957] In some embodiments, the substituted ring B is .

[00958] In some embodiments, the substituted ring B is .

[00959] In some embodiments, the substituted ring B is .

[00960] In some embodiments, the substituted ring B is .

[00961] In some embodiments, the substituted ring B is .

[00962] In some embodiments, the substituted ring B is

.

[00963] In some embodiments, the substituted ring B is .

[00964] In some embodiments, the substituted ring B is .

[00965] In some embodiments, the substituted ring B is .

[00966] In some embodiments, the substituted ring B is .

[00967] In some embodiments, the substituted ring B is .

[00968] In some embodiments, the substituted ring B is .

[00969] In some embodiments, the substituted ring B is

R6''

N R6'' R7 .

[00970] In some embodiments, the substituted ring B is .

[00971] In some embodiments, the substituted ring B is .

[00972] In some embodiments, the substituted ring B is .

[00973] In some embodiments, the substituted ring B is .

[00974] In some embodiments, the substituted ring B is .

[00975] In some embodiments, the substituted ring B is .

[00976] In some embodiments, the substituted ring B is

.

[00977] In some embodiments, the substituted ring B is .

[00978] In some embodiments, the substituted ring B is .

[00979] In some embodiments, the substituted ring B is .

[00980] In some embodiments, the substituted ring B is .

[00981] In some embodiments, the substituted ring B is .

[00982] In some embodiments, the substituted ring B is .

[00983] In some embodiments, the substituted ring B is .

[00984] In some embodiments, the substituted ring B is

.

[00985] In some embodiments, the substituted ring B is .

[00986] In some embodiments, the substituted ring B is .

[00987] In some embodiments, the substituted ring B is .

[00988] In some embodiments, the substituted ring B is .

[00989] In some embodiments, the substituted ring B is R6'' R7

N R6'' R7 .

[00990] In some embodiments, the substituted ring B is

.

[00991] In some embodiments, the substituted ring B is .

[00992] In some embodiments, the substituted ring B is .

[00993] In some embodiments, the substituted ring B is .

[00994] In some embodiments, the substituted ring B is .

No

[00995] In some embodiments, the substituted ring B is .

[00996] In some embodiments, the substituted ring B is

No.

[00997] In some embodiments, the substituted ring B is

No.

[00998] In some embodiments, the substituted ring B is

No.

[00999] In some embodiments, the substituted ring B is

No.

[001000] In some embodiments, the substituted ring B is

No.

[001001] In some embodiments, the substituted ring B is

No.

[001002] In some embodiments, the substituted ring B is

No.

[001003] In some embodiments, the substituted ring B is

No.

[001004] In some embodiments, the substituted ring B is

No. No

[001005] In some embodiments, the substituted ring B is .

No

[001006] In some embodiments, the substituted ring B is .

[001007] In some embodiments, the substituted ring B is

No.

[001008] In some embodiments, the substituted ring B is R6'' R7

No. R6''

No

[001009] In some embodiments, the substituted ring B is .

[001010] In some embodiments, the substituted ring B is

R 6''

No.

[001011] In some embodiments, the substituted ring B is

No.

[001012] In some embodiments, the substituted ring B is

F No.

[001013] In some embodiments, the substituted ring B is

No.

[001014] In some embodiments, the substituted ring B is

F No.

[001015] In some embodiments, the substituted ring B is

N F .

[001016] In some embodiments, the substituted ring B is selected

, , , , , , , CF 3 CF3 CF3

N N N , , , , , N N N N N , , , , ,

N N e .

[001017] In some embodiments, the substituted ring B is selected from the group consisting of: , , and (e.g., , and

).

[001018] In some embodiments, the substituted ring B is selected from the group consisting of: , , CF 3 CF3 CF3

N N N , , , , , N N N N N , , , , ,

N N e .

[001019] In some embodiments, the substituted ring B is selected from the group consisting of: , ,

, , , , , CF3

N N N , , , , ,

N N N N , , and .

[001020] In some embodiments, the substituted ring B is: R6 R6 R7 N O R7 .

[001021] In certain of these embodiments, the substituted ring B is: .

[001022] In some embodiments, the substituted ring B is .

[001023] In certain of these embodiments, the substituted ring B is .

[001024] In some embodiments, the substituted ring B is

.

[001025] In certain of these embodiments, the substituted ring B is . Ring B when Formula AA is Formula AA-2

[001026] In some embodiments, B is pyridyl or an N-oxide thereof (e.g., 2-pyridyl or an N-oxide thereof, 3-pyridyl or an N-oxide thereof, or 4-pyridyl or an N- oxide thereof).

[001027] In some embodiments, B is pyridyl (eg, 2-pyridyl, 3-pyridyl, or 4-pyridyl).

[001028] In some embodiments, B is a pyridyl N-oxide (e.g., 2-pyridyl N-oxide, 3-pyridyl N-oxide or 4-pyridyl N-oxide).

[001029] In some embodiments, B is pyrimidinyl or an N-oxide thereof (for example, 4-pyrimidinyl or an N-oxide thereof or 5-pyrimidinyl or an N-oxide thereof).

[001030] In some embodiments, B is pyridazinyl.

[001031] In some embodiments, B is pyrazinyl.

[001032] In some embodiments, B is triazinyl.

[001033] In some embodiments, B is a 6-membered heteroaryl including from 1 to 2 optionally substituted nitrogen atoms.

[001034] In some embodiments, B is an N-substituted pyridonyl (eg, N-substituted pyrid-2-on-4-yl).

[001035] In some embodiments, B is one of the rings disclosed hereinafter, substituted as hereinafter disclosed, wherein, in each case, the bond which is shown to be broken by the wavy line connects B to the NHC(O) group of Formula AA.

[001036] In some embodiments, the substituted ring B is .

[001037] In some embodiments, the substituted ring B is .

[001038] In some embodiments, the substituted ring B is .

[001039] In some embodiments, the substituted ring B is .

[001040] In some embodiments, the substituted ring B is .

[001041] In some embodiments, the substituted ring B is .

[001042] In some embodiments, the substituted ring B is .

[001043] In some embodiments, the substituted ring B is .

[001044] In some embodiments, the substituted ring B is .

[001045] In some embodiments, the substituted ring B is .

[001046] In some embodiments, the substituted ring B is R7 R7

N R6 .

[001047] In some embodiments, the substituted ring B is .

[001048] In some embodiments, the substituted ring B is .

[001049] In some embodiments, the substituted ring B is .

[001050] In some embodiments, the substituted ring B is .

[001051] In some embodiments, the substituted ring B is .

[001052] In some embodiments, the substituted ring B is .

[001053] In some embodiments, the substituted ring B is .

[001054] In some embodiments, the substituted ring B is .

[001055] In some embodiments, the substituted ring B is .

[001056] In some embodiments, the substituted ring B is .

[001057] In some embodiments, the substituted ring B is

.

[001058] In some embodiments, the substituted ring B is .

[001059] In some embodiments, the substituted ring B is .

[001060] In some embodiments, the substituted ring B is .

[001061] In some embodiments, the substituted ring B is .

[001062] In some embodiments, the substituted ring B is .

[001063] In some embodiments, the substituted ring B is .

[001064] In some embodiments, the substituted ring B is .

[001065] In some embodiments, the substituted ring B is .

[001066] In some embodiments, the substituted ring B is .

[001067] In some embodiments, the substituted ring B is .

[001068] In some embodiments, the substituted ring B is .

[001069] In some embodiments, the substituted ring B is .

[001070] In some embodiments, the substituted ring B is

.

[001071] In some embodiments, the substituted ring B is .

[001072] In some embodiments, the substituted ring B is .

[001073] In some embodiments, the substituted ring B is .

[001074] In some embodiments, the substituted ring B is .

[001075] In some embodiments, the substituted ring B is .

[001076] In some embodiments, the substituted ring B is .

[001077] In some embodiments, the substituted ring B is

.

[001078] In some embodiments, the substituted ring B is .

[001079] In some embodiments, the substituted ring B is .

[001080] In some embodiments, the substituted ring B is .

[001081] In some embodiments, the substituted ring B is .

[001082] In some embodiments, the substituted ring B is .

[001083] In some embodiments, the substituted ring B is .

[001084] In some embodiments, the substituted ring B is

.

[001085] In some embodiments, the substituted ring B is .

[001086] In some embodiments, the substituted ring B is .

[001087] In some embodiments, the substituted ring B is .

[001088] In some embodiments, the substituted ring B is .

[001089] In some embodiments, the substituted ring B is .

[001090] In some embodiments, the substituted ring B is

.

[001091] In some embodiments, the substituted ring B is .

No

[001092] In some embodiments, the substituted ring B is .

[001093] In some embodiments, the substituted ring B is

No.

[001094] In some embodiments, the substituted ring B is

No.

[001095] In some embodiments, the substituted ring B is

No.

[001096] In some embodiments, the substituted ring B is

No.

[001097] In some embodiments, the substituted ring B is

No.

[001098] In some embodiments, the substituted ring B is

No.

[001099] In some embodiments, the substituted ring B is

No.

[001100] In some embodiments, the substituted ring B is

No.

[001101] In some embodiments, the substituted ring B is

No. No

[001102] In some embodiments, the substituted ring B is .

No

[001103] In some embodiments, the substituted ring B is .

[001104] In some embodiments, the substituted ring B is

No.

[001105] In some embodiments, the substituted ring B is R6 R7

No. R6

No

[001106] In some embodiments, the substituted ring B is .

[001107] In some embodiments, the substituted ring B is R6

No.

[001108] In some embodiments, the substituted ring B is

No.

[001109] In some embodiments, the substituted ring B is

F No.

[001110] In some embodiments, the substituted ring B is

No.

[001111] In some embodiments, the substituted ring B is

F No.

[001112] In some embodiments, the substituted ring B is

N F .

[001113] In some embodiments, the substituted ring B is: R6 N R7 .

[001114] In some embodiments, the substituted ring B is:

N R7 R7 .

[001115] In some embodiments, the substituted ring B is selected from the group consisting of: , , , , , , ,

CF 3 CF3 CF3

N N N , , , , , N N N N N , , , , ,

N N e .

[001116] In some embodiments, the substituted ring B is selected from the group consisting of: , , and (eg, , and ).

[001117] In some embodiments, the substituted ring B is selected

swimming within the group consisting of: , , CF 3 CF3 CF3

N N N , , , , , N N N N N , , , , ,

N N e .

[001118] In some embodiments, the substituted ring B is selected from the group consisting of: , , , , , , , CF3

N N N , , , , ,

N N N N , , and .

[001119] In some embodiments, the substituted ring B is: R6 R6 R7 N O R7 .

[001120] In certain of these embodiments, the substituted ring B is: .

[001121] In some embodiments, the substituted ring B is .

[001122] In certain of these embodiments, the substituted ring B is .

[001123] In some embodiments, the substituted ring B is .

[001124] In certain of these embodiments, the substituted ring B is . Ring B when Formula AA is Formula AA-3

[001125] In some embodiments, B is pyridyl or an N-oxide thereof (e.g., 2-pyridyl or an N-oxide thereof, 3-pyridyl or an N-oxide thereof, or 4-pyridyl or an N- oxide thereof).

[001126] In some embodiments, B is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl).

[001127] In some embodiments, B is a pyridyl N-oxide (e.g., 2-pyridyl N-oxide, 3-pyridyl N-oxide or 4-pyridyl N-oxide).

[001128] In some embodiments, B is pyrimidinyl or an N-oxide thereof (for example, 4-pyrimidinyl or an N-oxide thereof or 5-pyrimidinyl or an N-oxide thereof).

[001129] In some embodiments, B is pyridazinyl.

[001130] In some embodiments, B is pyrazinyl.

[001131] In some embodiments, B is triazinyl.

[001132] In some embodiments, B is one of the rings disclosed hereinafter, substituted as hereinafter disclosed, wherein, in each case, the bond which is shown to be broken by the wavy line connects B to the NHC(O) group of Formula AA.

[001133] In some embodiments, the substituted ring B is .

[001134] In some embodiments, the substituted ring B is .

[001135] In some embodiments, the substituted ring B is .

[001136] In some embodiments, the substituted ring B is .

[001137] In some embodiments, the substituted ring B is .

[001138] In some embodiments, the substituted ring B is .

[001139] In some embodiments, the substituted ring B is .

[001140] In some embodiments, the substituted ring B is .

[001141] In some embodiments, the substituted ring B is .

[001142] In some embodiments, the substituted ring B is .

[001143] In some embodiments, the substituted ring B is R7 R7

N R6 .

[001144] In some embodiments, the substituted ring B is

.

[001145] In some embodiments, the substituted ring B is .

[001146] In some embodiments, the substituted ring B is .

[001147] In some embodiments, the substituted ring B is .

[001148] In some embodiments, the substituted ring B is .

[001149] In some embodiments, the substituted ring B is .

[001150] In some embodiments, the substituted ring B is .

[001151] In some embodiments, the substituted ring B is

.

[001152] In some embodiments, the substituted ring B is .

In some embodiments, the substituted ring B is .

[001153] In some embodiments, the substituted ring B is .

[001154] In some embodiments, the substituted ring B is .

[001155] In some embodiments, the substituted ring B is .

[001156] In some embodiments, the substituted ring B is .

[001157] In some embodiments, the substituted ring B is

.

[001158] In some embodiments, the substituted ring B is .

[001159] In some embodiments, the substituted ring B is .

[001160] In some embodiments, the substituted ring B is .

[001161] In some embodiments, the substituted ring B is .

[001162] In some embodiments, the substituted ring B is .

[001163] In some embodiments, the substituted ring B is .

[001164] In some embodiments, the substituted ring B is .

[001165] In some embodiments, the substituted ring B is .

[001166] In some embodiments, the substituted ring B is .

[001167] In some embodiments, the substituted ring B is .

[001168] In some embodiments, the substituted ring B is .

[001169] In some embodiments, the substituted ring B is .

[001170] In some embodiments, the substituted ring B is .

[001171] In some embodiments, the substituted ring B is

.

[001172] In some embodiments, the substituted ring B is .

[001173] In some embodiments, the substituted ring B is .

[001174] In some embodiments, the substituted ring B is .

[001175] In some embodiments, the substituted ring B is .

[001176] In some embodiments, the substituted ring B is .

[001177] In some embodiments, the substituted ring B is .

[001178] In some embodiments, the substituted ring B is

.

[001179] In some embodiments, the substituted ring B is .

[001180] In some embodiments, the substituted ring B is .

[001181] In some embodiments, the substituted ring B is .

[001182] In some embodiments, the substituted ring B is .

[001183] In some embodiments, the substituted ring B is .

[001184] In some embodiments, the substituted ring B is

.

[001185] In some embodiments, the substituted ring B is .

[001186] In some embodiments, the substituted ring B is .

[001187] In some embodiments, the substituted ring B is .

No

[001188] In some embodiments, the substituted ring B is .

[001189] In some embodiments, the substituted ring B is

No.

[001190] In some embodiments, the substituted ring B is

No.

[001191] In some embodiments, the substituted ring B is

No.

[001192] In some embodiments, the substituted ring B is

No.

[001193] In some embodiments, the substituted ring B is

No.

[001194] In some embodiments, the substituted ring B is

No.

[001195] In some embodiments, the substituted ring B is

No.

[001196] In some embodiments, the substituted ring B is

No. No

[001197] In some embodiments, the substituted ring B is .

No

[001198] In some embodiments, the substituted ring B is .

[001199] In some embodiments, the substituted ring B is

No.

[001200] In some embodiments, the substituted ring B is R6 R7

No. R6

No

[001201] In some embodiments, the substituted ring B is .

[001202] In some embodiments, the substituted ring B is R6

No.

[001203] In some embodiments, the substituted ring B is

No.

[001204] In some embodiments, the substituted ring B is

F No.

[001205] In some embodiments, the substituted ring B is

No.

[001206] In some embodiments, the substituted ring B is

F No.

[001207] In some embodiments, the substituted ring B is

N F .

[001208] In some embodiments, the substituted ring B is selected from the group consisting of: , , , , , , ,

CF 3 CF3 CF3

N N N , , , , , N N N N N , , , , ,

N N e .

[001209] In some embodiments, the substituted ring B is selected from the group consisting of: , , and (eg, , and ).

[001210] In some embodiments, the substituted ring B is selected

swimming within the group consisting of: , , CF 3 CF3 CF3

N N N , , , , , N N N N N , , , , ,

N N e .

[001211] In some embodiments, the substituted ring B is selected from the group consisting of: , , , , , , , CF3

N N N , , , , ,

N N N N , , and . Ring B' when Formula AA is Formula AA-4

[001212] In some embodiments, B' is 2-pyridyl or 3-pyridyl, or an N-oxide thereof.

[001213] In some embodiments, B' is 2-pyridyl.

[001214] In some embodiments, B' is 3-pyridyl.

[001215] In some embodiments, B' is 2-pyridyl N-oxide.

[001216] In some embodiments, B' is 3-pyridyl N-oxide.

[001217] In some embodiments, B' is one of the rings disclosed hereinafter, substituted as disclosed hereinafter, wherein, in each case, the bond that is shown to be broken by the wavy line connects B' to the NHC(O) group of Formula AA.

[001218] In some embodiments, the substituted ring B' is .

[001219] In some embodiments, the substituted ring B' is .

[001220] In some embodiments, the substituted ring B' is .

[001221] In some embodiments, the substituted ring B' is

.

[001222] In some embodiments, the substituted ring B' is .

[001223] In some embodiments, the substituted ring B' is .

[001224] In some embodiments, the substituted ring B' is .

[001225] In some embodiments, the substituted ring B' is .

[001226] In some embodiments, the substituted ring B' is .

[001227] In some embodiments, the substituted ring B' is .

[001228] In some embodiments, the substituted ring B' is .

[001229] In some embodiments, the substituted ring B' is .

[001230] In some embodiments, the substituted ring B' is .

[001231] In some embodiments, the substituted ring B' is .

[001232] In some embodiments, the substituted ring B' is .

[001233] In some embodiments, the substituted ring B' is .

[001234] In some embodiments, the substituted ring B' is

.

[001235] In some embodiments, the substituted ring B' is .

[001236] In some embodiments, the substituted ring B' is .

[001237] In some embodiments, the substituted ring B' is .

[001238] In some embodiments, the substituted ring B' is .

[001239] In some embodiments, the substituted ring B' is .

[001240] In some embodiments, the substituted ring B' is .

[001241] In some embodiments, the substituted ring B' is

.

[001242] In some embodiments, the substituted ring B' is .

[001243] In some embodiments, the substituted ring B' is .

[001244] In some embodiments, the substituted ring B' is .

[001245] In some embodiments, the substituted ring B' is .

[001246] In some embodiments, the substituted ring B' is .

[001247] In some embodiments, the substituted ring B' is .

[001248] In some embodiments, the substituted ring B' is .

[001249] In some embodiments, the substituted ring B' is .

[001250] In some embodiments, the substituted ring B' is .

[001251] In some embodiments, the substituted ring B' is .

[001252] In some embodiments, the substituted ring B' is .

[001253] In some embodiments, the substituted ring B' is .

[001254] In some embodiments, the substituted ring B' is

.

[001255] In some embodiments, the substituted ring B' is .

[001256] In some embodiments, the substituted ring B' is .

[001257] In some embodiments, the substituted ring B' is

No.

[001258] In some embodiments, the substituted ring B' is

F No.

[001259] In some embodiments, the substituted ring B' is .

[001260] In some embodiments, the substituted ring B' is: R6 N R7 .

[001261] In some embodiments, the substituted ring B' is:

N R7 7 R .

[001262] In some embodiments, the substituted ring B' is .

[001263] In certain of these embodiments, the substituted ring B' is .

[001264] In some embodiments, the substituted ring B' is .

[001265] In certain of these embodiments, the substituted ring B' is . The B'' Ring

[001266] In some embodiments, B'' is 4-pyridyl.

[001267] In some embodiments, B'' is 4-pyridyl N-oxide.

[001268] In some embodiments, B'' is one of the rings disclosed hereinafter, substituted as disclosed hereinafter, wherein, in each case, the bond that is shown to be broken by the wavy line connects B'' to the NHC(O) group of Formula AA.

[001269] In some embodiments, the substituted ring B'' is .

[001270] In some embodiments, the substituted ring B'' is .

[001271] In some embodiments, the substituted ring B'' is .

[001272] In some embodiments, the substituted ring B'' is .

[001273] In some embodiments, the substituted ring B'' is .

[001274] In some embodiments, the substituted ring B'' is .

[001275] In some embodiments, the substituted ring B'' is .

[001276] In some embodiments, the substituted ring B'' is .

[001277] In some embodiments, the substituted ring B'' is

.

[001278] In some embodiments, the substituted ring B'' is .

[001279] In some embodiments, the substituted ring B'' is .

[001280] In some embodiments, the substituted ring B'' is .

[001281] In some embodiments, the substituted ring B'' is .

[001282] In some embodiments, the substituted ring B'' is .

[001283] In some embodiments, the substituted ring B'' is .

[001284] In some embodiments, the substituted ring B'' is

.

[001285] In some embodiments, the substituted ring B'' is .

No

[001286] In some embodiments, the substituted ring B'' is .

[001287] In some embodiments, the substituted ring B'' is

No.

[001288] In some embodiments, the substituted ring B'' is

No.

[001289] In some embodiments, the substituted ring B'' is

No.

[001290] In some embodiments, the substituted ring B'' is

No.

[001291] In some embodiments, the substituted ring B'' is

No.

[001292] In some embodiments, the substituted ring B'' is

No.

[001293] In some embodiments, the substituted ring B'' is

No.

[001294] In some embodiments, the substituted ring B'' is

No.

[001295] In some embodiments, the substituted ring B'' is

No. No

[001296] In some embodiments, the substituted ring B'' is .

No

[001297] In some embodiments, the substituted ring B'' is .

[001298] In some embodiments, the substituted ring B'' is

No.

[001299] In some embodiments, the substituted ring B'' is R6' R 7'

No. R6'

No

[001300] In some embodiments, the substituted ring B'' is .

[001301] In some embodiments, the substituted ring B'' is R 6'

No.

[001302] In some embodiments, the substituted ring B'' is selected from the group consisting of: , , , , , , , CF3

N N N N N , , , and .

[001303] In some embodiments, the substituted ring B'' is selected from the group consisting of: , , , , , , , CF 3 CF3 CF3

N N N N , , , , ,

N N N N , , and .

[001304] In some embodiments, the substituted ring B'' is selected from the group consisting of: , , and (eg, , , ).

[001305] In some embodiments, the substituted ring B'' is selected from the group consisting of: , ,

CF 3 CF3 CF3

N N N N , , , , ,

N N N N , , and .

[001306] In some embodiments, the substituted ring B'' is: .

[001307] In certain of these embodiments, the substituted ring B'' is: . Groups R6, R6', R6'', R7 and R7' Groups R6 and R7

[001308] In some embodiments, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1 -C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), C6-C10 aryl, 5 to 5 membered heteroaryl 10 membered, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered and C2-membered heterocycloalkyl -C6 alkenyl.

[001309] In some embodiments, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cy-

cloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl 5 to 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl with 5 to 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001310] In some embodiments, R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2 , NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl) , NHCOC1-C6 alkyl, NHCOC6-C1 0 aryl, NHCO (5 to 10 membered heteroaryl),

NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy - droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001311] In some embodiments, R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5-membered heteroaryl 10-membered, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl,

S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3 to 10 membered heterocycloalkyl and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(heterocycloalkyl with 3 to 7 members), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001312] In some embodiments, R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2 , NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl) , NHCOC1-C6 alkyl, NHCOC6-C1 0 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001313] In some embodiments, R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5-membered heteroaryl and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO- OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO( 3 to 7 members), NHCOC1-C6 alky yl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl),

NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001314] In some embodiments, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.

[001315] In some embodiments, each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.

[001316] In some embodiments, each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.

[001317] In some embodiments, each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl. For example, each R6 is isopropyl.

[001318] In some embodiments, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl alkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001319] In some embodiments, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.

[001320] In some embodiments, each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.

[001321] In some embodiments, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001322] In some embodiments, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001323] In certain embodiments (when a pair of R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one heterocyclic ring with 5 to 8 members containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9), the C4-C8 carbocyclic ring is a C5 carbocyclic optionally substituted by one or more oxo, CH3 or hydroxy. For example, the C5 carbocyclic ring is replaced by a CH3. For example, the C5 carbocyclic ring is geminally substituted by two CH3.

[001324] In certain embodiments (when a pair of R6 and R7 on adjacent atoms, considered together with the atoms that co-

nectate the same independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9), the C4-C8 carbocyclic ring is a C7 carbocyclic ring, where the C7 carbocyclic ring is a bicyclic spirocycle, where the bicyclic spirocycle comprises a ring with 5 members and a ring with 3 members.

[001325] In some embodiments, each of R6 and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. Groups R6'' and R7 when Formula AA is Formula AA-1

[001326] In some embodiments of the compound of Formula AA-1, R6'' is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2Cl -C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl,

OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6'' is optionally substituted by one or more substituents independently selected from hydroxy , halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6'' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6'' is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6'' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more independently selected substituents among hi-

hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001327] In some embodiments of the compound of Formula AA-1, each R6'' is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001328] In some embodiments of the compound of Formula AA-1, each R6'' is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.

[001329] In some embodiments of the compound of Formula AA-1, each R6'' is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.

[001330] In some embodiments of the compound of Formula AA-1, each R6'' is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl. For example, each R6'' is isopropyl.

[001331] In some embodiments of the compound of Formula AA-1, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001332] In some embodiments of the compound of Formula AA-1, R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1 - C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, heteroaryl with 5 to 10 members, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and heterocycloalkyl with 3 to 10 members and C2-C6 alkenyl.

[001333] In some embodiments of the compound of Formula AA-1, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.

[001334] In some embodiments of the compound of Formula AA-1, each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl.

[001335] In some embodiments of the compound of Formula AA-1,

a pair of R6'' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy , hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001336] In some embodiments of the compound of Formula AA-1, a pair of R6'' and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, in that the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001337] In certain embodiments of the compound of Formula AA-1 (when a pair of R6'' and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 ring carbocyclic or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9), the C4-C8 carbocyclic ring is a C5 carbocyclic optionally substituted by one or more oxo, CH3 or hydroxy. For example, the C5 carbocyclic ring is replaced by a CH3. For example, the C5 carbocyclic ring is geminally substituted by two CH3.

[001338] In certain embodiments of the compound of Formula AA-1 (when a pair of R6'' and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 ring carbocyclic or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9), the C4-C8 carbocyclic ring is a C7 carbocyclic, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.

[001339] In some embodiments of the compound of Formula AA-1, R6'' is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2Cl -C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl , NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6'' is optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 to 7 members, C6-C10 aryl, hetero-

5-10 membered aryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl 5- to 10-membered), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6'' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6'' is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl.

[001340] In some embodiments of the compound of Formula AA-1, R6'' is selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, NO2, COC1-C6 alkyl, CO2C1 -C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl , NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6'' is optionally substituted by one or more substituents independently selected from hydroxy, Cl, Br, I, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl,

OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(3-7 membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6'' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6'' is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; R7 is selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1- C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6 - C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6- C10 aryl, OCO(5 to 10 membered heteroaryl),

OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6'' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001341] In some embodiments of the compound of Formula AA-1, R6'' is selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl , CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl,

5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, wherein R6'' is optionally substituted by one or more substituents independently selected from hydroxy, Cl, Br, I, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl members), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6- C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6'' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6'' is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; R7 is selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl,

C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO( 5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(3-7 membered heterocycloalkyl), NHCOC2- C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6'' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001342] In some embodiments, each of R6'' and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or a pair of R6'' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. Groups R6 and R7 when Formula AA is Formula AA-2

[001343] In some embodiments of the compound of Formula AA-2, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2 , COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl , 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3-membered heterocycloalkyl 10-membered and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, = NR10, CO-OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-

C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001344] In some embodiments of the compound of Formula AA-2, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl -

la, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5-membered heteroaryl 10-membered, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO- OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO( 3 to 7 membered), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(3 to 7 membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2) C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001345] In some embodiments of the compound of Formula AA-2, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, C6-C10 aryl, 5 to 10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl 5 to 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl with 5 to 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001346] In some embodiments of the compound of Formula AA-2, each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.

[001347] In some embodiments of the compound of Formula AA-2, each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6-C10 aryl.

[001348] In some embodiments of the compound of Formula AA-2, each R6 is independently selected from the group consisting of

te in: C1-C6 alkyl and C3-C7 cycloalkyl.

[001349] In some embodiments of the compound of Formula AA-2, each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl. For example, each R6 is isopropyl.

[001350] In some embodiments of the compound of Formula AA-2, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001351] In some embodiments of the compound of Formula AA-2, each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6-C10 aryl.

[001352] In some embodiments of the compound of Formula AA-2, each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl.

[001353] In some embodiments of the compound of Formula AA-2, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001354] In some embodiments of the compound of Formula AA-2, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6- C10 aryl and CONR8R9.

[001355] In certain embodiments of the compound of Formula AA-2 (when a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the ring heterocyclyl is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9) , the C4 -C8 carbocyclic ring is a C5 carbocyclic optionally substituted by one or more oxo, CH3 or hydroxy. For example, the C5 carbocyclic ring is replaced by a CH3. For example, the C5 carbocyclic ring is geminally substituted by two CH3.

[001356] In certain embodiments of the compound of Formula AA-2 (when a pair of R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the ring heterocyclyl is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9) , the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.

[001357] In some embodiments, each of R6 and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. Groups R6 and R7 when Formula AA is Formula AA-3

[001358] In some embodiments of the compound of Formula AA-3, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2 ,

COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl 10-membered and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10 , CO-OC1-C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO (3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S (O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001359] In some embodiments of the compound of Formula AA-3, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl - la, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, heteroaryl with 5 to 10 membered, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3 to 10 membered heterocycloalkyl and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO - OC1-C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(heterocycloalkyl with 3 to 7 members), NHCO C1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two independent heteroatoms

carefully selected among oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001360] In some embodiments of the compound of Formula AA-3, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, C6-C10 aryl, 5 to 10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl 5 to 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl,

NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001361] In some embodiments of the compound of Formula AA-3, each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.

[001362] In some embodiments of the compound of Formula AA-3, each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.

[001363] In some embodiments of the compound of Formula AA-3, each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl. For example, each R6 is isopropyl.

[001364] In some embodiments of the compound of Formula AA-3, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001365] In some embodiments of the compound of Formula AA-3, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.

[001366] In some embodiments of the compound of Formula AA-3, each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl.

[001367] In some embodiments of the compound of Formula AA-3, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001368] In some embodiments of the compound of Formula AA-3, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, in which the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6- C10 aryl and CONR8R9.

[001369] In certain embodiments of the compound of Formula AA-3 (when a pair of R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the ring heterocyclyl is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9) , the C4 -C8 carbocyclic ring is a C5 carbocyclic optionally substituted by one or more oxo, CH3 or hydroxy. For example, the C5 carbocyclic ring is replaced by a CH3. For example, the C5 carbocyclic ring is geminally substituted by two CH3.

[001370] In certain embodiments of the compound of Formula AA-3 (when a pair of R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the ring heterocyclyl is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9) , the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, which comprises a 5-membered ring and a 3-membered ring.

[001371] In some embodiments, each of R6 and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. Groups R6 and R7 when Formula AA is Formula AA-4

[001372] In some embodiments of the compound of Formula AA-4, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2 , COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl , 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3-membered heterocycloalkyl 10-membered and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, = NR10, CO-OC1-C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(heterocycloalkyl with 3 to 7 m and alkyl, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001373] In some embodiments of the compound of Formula AA-4, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl - la, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, heteroaryl with 5 to 10 membered, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3 to 10 membered heterocycloalkyl and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO - OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-

C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(3 to 7 membered heterocycloalkyl members), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001374] In some embodiments of the compound of Formula AA-4, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, C6-C10 aryl, heteroaryl with 5 to 10 mem-

bros, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl 5 to 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl with 5 to 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001375] In some embodiments of the compound of Formula AA-4, each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.

[001376] In some embodiments of the compound of Formula AA-4, each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl.

[001377] In some embodiments of the compound of Formula AA-4, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001378] In some embodiments of the compound of Formula AA-4, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.

[001379] In some embodiments of the compound of Formula AA-4, each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro and phenyl.

[001380] In some embodiments, each of R6 and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. Groups R6' and R7' when Formula AA is Formula AA-5

[001381] In some embodiments of the compound of Formula AA-5, R6' and R7' are each independently selected from C1-C6 unbranched alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy , halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3-membered heterocycloalkyl) 7 membered), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 3- to 10-membered alkyl, C3-C10 cycloalkyl and heterocycloalkyl, and C2-C6 alkenyl, wherein R6' and R7' are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1 -C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(heteroaryl with 5 to 10 members), OCO(heterocycloalkyl c with 3 to 7 members), C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy by which R6' or R7' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6' or R7' is optionally fused to a carbocyclic ring or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more independently selected substituents among hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001382] In some embodiments of the compound of Formula AA-5, R6' and R7' are each independently selected from C2-C6 unbranched alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy , I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3-membered heterocycloalkyl 7 membered), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 3- to 10-membered alkyl, C3-C10 cycloalkyl and heterocycloalkyl, and C2-C6 alkenyl, wherein R6' and R7' are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo , C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO (5- to 10-membered heteroaryl), OCO (heterocycloalkyl with m 3 to 7 members), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(3 to 7 membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2 )C1-C6 alkyl; and wherein p C1-C6 alkoxy by which R6' or R7' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6' or R7' is optionally fused to a car ring - bocyclic or five- to seven-membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl;

or a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001383] In some embodiments of the compound of Formula AA-5, R6' and R7' are each independently selected from C2-C6 unbranched alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl 10-membered and C2-C6 alkenyl, wherein R6' and R7' are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1- C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO( 3 to 7 members), NHCO C1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein p C1-C6 alkoxy by which R6' or R7' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or

NR8R9, or wherein R6' or R7' is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001384] In some embodiments of the compound of Formula AA-5, each R6' is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the unbranched C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocyclo-

4 to 6 membered alkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl) , NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001385] In some embodiments of the compound of Formula AA-5, each R6' is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.

[001386] In some embodiments of the compound of Formula AA-5, each R6' is independently selected from the group consisting of: C1-C6 unbranched alkyl and C3-C7 cycloalkyl.

[001387] In some embodiments of the compound of Formula AA-5, each R6' is independently selected from the group consisting of: methyl, cyclopropyl, fluoro and phenyl.

[001388] In some embodiments of the compound of Formula AA-5, each R7' is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy , halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6- C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl members) and NHCOC2-C6 alkynyl.

[001389] In some embodiments of the compound of Formula AA-5, each R7' is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.

[001390] In some embodiments of the compound of Formula AA-5, each R7' is independently selected from the group consisting of: methyl, cyclopropyl, fluoro and phenyl.

[001391] In some embodiments of the compound of Formula AA-5, a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or hetero- ring cyclic is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001392] In some embodiments of the compound of Formula AA-5, a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, in that the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001393] In certain embodiments of the compound of Formula AA-5 (when a pair of R6' and R7' on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 ring carbocyclic or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9), the C4-C8 carbocyclic ring is a C5 carbocyclic optionally substituted by one or more oxo, CH3 or hydroxy. For example, the C5 carbocyclic ring is replaced by a CH3. For example, the C5 carbocyclic ring is geminally substituted by two CH3.

[001394] In certain embodiments of the compound of Formula AA-5 (when a pair of R6' and R7' on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 ring carbocyclic or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9), the C4-C8 carbocyclic ring is a C7 carbocyclic, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the comprises a 5-membered ring and a 3-membered ring.

[001395] In some embodiments, each of R6' and R7' is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or a pair of R6' and R7' on adjacent atoms, considered together with the atoms connecting them, independently-

form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, = NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. The R3 group

[001396] In some embodiments, R3 is selected from hydrogen, C1-C6 alkyl and , wherein the C1-C2 alkylene group is optionally substituted with oxo.

[001397] In some embodiments, R3 is hydrogen.

[001398] In some embodiments, R3 is different from hydrogen.

[001399] In some embodiments, R3 is cyan.

[001400] In some embodiments, R3 is hydroxy.

[001401] In some embodiments, R3 is C1-C6 alkoxy.

[001402] In some embodiments, R3 is C1-C6 alkyl.

[001403] In some embodiments, R3 is methyl.

[001404] In some embodiments, R3 is , wherein the C1-C2 alkylene group is optionally substituted by oxo.

[001405] In some embodiments, R3 is -CH2R14.

[001406] In some embodiments, R3 is -C(O)R14. In certain of these embodiments, R3 is CHO. In certain other such embodiments, R3 is C(O)C1-C6 alkyl.

[001407] In some embodiments, R3 is -CH2CH2R14.

[001408] In some embodiments, R3 is -CHR14CH3.

[001409] In some embodiments, R3 is -CH2C(O)R14.

[001410] In some embodiments, R3 is -C(O)CH2R14.

[001411] In some embodiments, R3 is CO2C1-C6 alkyl (eg CO2t-Bu). The R14 group

[001412] In some embodiments, R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, or monocyclic or bicyclic C6-C10 aryl, wherein each C1-C6 alkyl, aryl, or heteroaryl is optionally independently replaced by 1 or 2 R6.

[001413] In some embodiments, R14 is hydrogen or C1-C6 alkyl.

[001414] In some embodiments, R14 is hydrogen, 5- to 10-membered monocyclic or bicyclic heteroaryl, or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl, or heteroaryl is optionally independently substituted by 1 or 2 R6.

[001415] In some embodiments, R14 is hydrogen.

[001416] In some embodiments, R14 is C1-C6 alkyl.

[001417] In some embodiments, R14 is methyl.

[001418] In some embodiments, R14 is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted independently by 1 or 2 R6.

[001419] In some embodiments, R14 is C6-C10 monocyclic or bicyclic aryl optionally independently substituted by 1 or 2 R6. The chemical moiety S(=O)(NHR3)=N-

[001420] In some embodiments, the sulfur in the chemical moiety S(=O)(NHR3)=N- has (S) stereochemistry.

[001421] In some embodiments, the sulfur in the chemical moiety S(=O)(NHR3)=N- has (R) stereochemistry. The R10 group

[001422] In some embodiments, R10 is C1-C6 alkyl.

[001423] In some embodiments, R10 is methyl.

[001424] In some embodiments, R10 is ethyl. The R8 and R9 groups

[001425] In some embodiments, each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, (C=NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13 , CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl ; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached.

[001426] In some embodiments, each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, (C=NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13 , CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl ; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached.

[001427] In some embodiments, each of R8 and R9 at each occurrence is hydrogen.

[001428] In some embodiments, each R8 in each occurrence is hydrogen and each R9 in each occurrence is C1-C6 alkyl.

[001429] In some embodiments, each R8 at each occurrence is hydrogen and each R9 at each occurrence is methyl.

[001430] In some embodiments, each R8 in each occurrence is hydrogen and each R9 in each occurrence is ethyl.

[001431] In some embodiments, each of R8 and R9 at each occurrence is methyl.

[001432] In some embodiments, each of R8 and R9 in each occurrence is ethyl.

[001433] In some embodiments, R8 and R9, taken together with the nitrogen to which they are attached, form a 3-membered ring.

[001434] In some embodiments, R8 and R9, taken together with the nitrogen to which they are attached, form a 4-membered ring.

[001435] In some embodiments, R8 and R9, taken together with the nitrogen to which they are attached, form a 5-membered ring.

[001436] In some embodiments, R8 and R9, taken together with the nitrogen to which they are attached, form a 6-membered ring optionally containing one or more oxygen atoms in addition to the nitrogen to which they are attached.

[001437] In some embodiments, R8 and R9, taken together with the nitrogen to which they are attached, form a 6-membered ring optionally containing one or more nitrogen atoms in addition to the nitrogen to which they are attached.

[001438] In some embodiments, R8 and R9, taken together with the nitrogen to which they are attached, form a 7-membered ring.

[001439] In some embodiments, one of R8 and R9 is C(O)R13; R13 is -(Z1-Z2)a1-Z3; and a1 is 0.

[001440] In certain of these embodiments, the other of R8 and R9 is hydrogen.

[001441] As a non-limiting example of the foregoing modalities

res, NR8R9 is selected from the group consisting of: NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001442] In some embodiments, one of R8 and R9 is C(O)R13; R13 is C1-C6 alkyl.

[001443] In certain embodiments, NR8R9 is selected from the group consisting of: NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl with 5 to 10 members), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, and NH(C=NR13)NR11R12.

[001444] In certain embodiments, NR8R9 is selected from the group consisting of: NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl with 5 to 10 members), NHCO(3 to 7 membered heterocycloalkyl), NHCOC2-C6 alkynyl and NHCOOC1-C6 alkyl. The R13 group

[001445] In some embodiments, R13 is C1-C6 alkyl.

[001446] In some embodiments, R13 is methyl.

[001447] In some embodiments, R13 is ethyl.

[001448] In some embodiments, R13 is C6-C10 aryl.

[001449] In some embodiments, R13 is phenyl.

[001450] In some embodiments, R13 is heteroaryl with 5 to 10 members.

[001451] In some embodiments, R13 is -(Z1-Z2)a1-Z3.

[001452] In certain of these embodiments, a1 is 0. In certain embodiments, Z3 is C6-C10 aryl or heteroaryl with 5 to 10 members.

[001453] In some embodiments, R13 is C6-C10 aryl.

[001454] In some embodiments, R13 is phenyl.

[001455] In some embodiments, R13 is heteroaryl with 5 to 10 members.

[001456] In some embodiments, C(O)R13 is selected from COC1-C6 alkyl, CO-C6-C10 aryl and CO(5 to 10 membered heteroaryl). The groups R11 and R12

[001457] In some embodiments, each of R11 and R12 at each occurrence is independently selected from hydrogen and C1-C6 alkyl.

[001458] In some embodiments, each of R11 and R12 at each occurrence is hydrogen.

[001459] In some embodiments, each R11 in each occurrence is hydrogen and each R12 in each occurrence is C1-C6 alkyl.

[001460] In some embodiments, each R11 in each occurrence is hydrogen and each R12 in each occurrence is methyl.

[001461] In some embodiments, each R11 in each occurrence is hydrogen and each R12 in each occurrence is ethyl.

[001462] In some embodiments, each of R11 and R12 at each occurrence is methyl.

[001463] In some embodiments, each of R11 and R12 in each occurrence is ethyl. The R15 Group

[001464] In some embodiments, R15 is -(Z4-Z5)a2-Z6.

[001465] In certain embodiments, a2 is 1 to 5.

[001466] In certain embodiments, the Z4 group linked directly to R1 or R2 is -O-.

[001467] In certain embodiments, each Z4 is independently -O- or -NH-, provided that the Z4 group directly attached to R1 or R2 is -O-.

[001468] In certain embodiments, each Z4 is -O-.

[001469] In certain embodiments, each Z5 is independently C2-C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxyl. In certain such embodiments, each Z5 is independently C2-C4 (eg, C2-C3 (eg, C2 or C3)) alkylene.

[001470] In certain embodiments, Z6 is OH.

[001471] In certain embodiments, Z6 is NHC(O)(C1-C6 alkoxy).

[001472] In certain embodiments, Z6 is C6-C10 aryl.

[001473] In certain embodiments, Z6 is C1-C6 alkoxy.

[001474] In certain embodiments of R15, a2=1; and Z4 is O. In certain such embodiments, Z5 is C2-C4 (e.g., C2-C3 (e.g., C2 or C3)) alkylene. In certain of the foregoing embodiments, Z6 is selected from OH, NHC(O)(C1-C6 alkoxy), and C1-C6 alkoxy.

[001475] As non-limiting examples, R15 is selected from: , , and .

[001476] In certain embodiments of R15, a2=1; and each Z4 is O. In certain such embodiments, Z5 is C2-C4 (e.g., C2-C3 (e.g., C2 or C3)) alkylene. In certain of the foregoing embodiments, Z6 is selected from OH, NHC(O)(C1-C6 alkoxy), and C1-C6 alkoxy. In certain other of the foregoing embodiments, Z6 is C6-C10 aryl (e.g., R15 is ).

[001477] In certain embodiments of R15, a2 ≥2 (eg, a2 is 3 or 4); each Z4 is O; and each Z5 is ethylene. In certain of these embodiments Z6 is OH. In certain other embodiments, Z6 is NHC(O)(C1-C6 alkoxy) (e.g., Boc). As a non-limiting example, R15 is: . Non-Limiting Combinations

[001478] In some embodiments, the A ring is the 5-membered heteroaryl containing two or more heteroatoms (e.g., two), each independently selected from N, O, and S (e.g.,

eg, N and S); m is 1; and n is 0 or 1. In certain such embodiments, ring A is thiazolyl (eg, thiazol-5-yl) or pyrazolyl (eg, pyrazol-3-yl).

[001479] In certain embodiments (when ring A is a 5-membered heteroaryl containing two or more heteroatoms, each independently selected from N, O, and S (e.g., N and S); m is 1; en is 0 or 1), R1 is C1-C6 (e.g. C2-C4) alkyl optionally substituted by one or more substituents each independently selected from hydroxy, NR8R9 and halo (e.g. hydroxy). In certain of these embodiments, n is 1; and R2 is halo (e.g. F). In certain other embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy.

[001480] In some embodiments, ring A is a 5-membered heteroaryl containing a ring sulfur atom and optionally one or more nitrogen atoms; m is 1; and n is 0 or 1. In certain such embodiments, ring A is thiophenyl or thiazolyl (eg, thiazolyl (eg, thiazol-5-yl)).

[001481] In certain embodiments (when ring A is a 5-membered heteroaryl containing a ring sulfur atom; m is 1; en is 0 or 1), R1 is C1-C6 alkyl optionally substituted by one or more substituents, each independently selected from hydroxy, NR8R9 and halo (e.g. hydroxy). In certain of these embodiments, n is 1; and R2 is halo (e.g. F). In certain other embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy.

[001482] In some embodiments, the A ring is thiazolyl (eg, thiazol-5-yl); m is 1; and n is 0 or 1. In certain such embodiments, R1 is C1-C6 alkyl optionally substituted by one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is or . In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy. In certain other embodiments, n is 0.

[001483] In some embodiments, ring A is pyrazolyl; m is 1; and n is 0 or 1. In certain such embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted by one or more halo (e.g., 0, 1, 2, or 3 (e.g., 0 , 2 or 3)). In certain of the foregoing modalities, R2 is halo (eg, F).

[001484] In some embodiments, A is thiazolyl (eg, 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted by hydroxy (e.g. 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted by hydroxyl (e.g. methyl, hydroxymethyl or hydroxyethyl).

[001485] In some embodiments, A is pyrazolyl (eg, 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted by 1 to 3 halo (e.g. fluoro).

[001486] In some embodiments, A is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted by NR8R9 (e.g. dimethylamino); and R2, when present, is halo (e.g., fluoro).

[001487] In some embodiments, A is thiophenyl (eg, 2-thiophenyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. isopropyl, 2-hydroxy-2-propyl or 1-propanoyl).

[001488] In some embodiments of one or more Formulas descri- (Y)q

As used herein, substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring. In certain of these embodiments, q is 0; and r is 1 or 2.

[001489] For example, the substituted ring B is selected from:

Huh

N (for example, , and ).

[001490] In some embodiments of one or more Formulas descri- (Y)q

In the (R7 )pts herein, the substituted ring B is; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring. In certain of these modalities, q is

0.

[001491] In certain of the foregoing embodiments, the substituted ring B is selected from the group consisting of: , CF 3 CF3

N N , , , , , CF3

N N N N N , , , , ,

N N N , e.g.

[001492] For example, substituted ring B is selected from: CF3

No N N , , , , ,

N N N , e.g.

[001493] In some embodiments, the substituted ring B is

(Y)q

N(Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring.

[001494] In some embodiments, the substituted ring B is (Y)q

N(R7)p; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring. R6

N R6(R7)p

[001495] In some embodiments, the substituted ring B is ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.

R6

N 7

[001496] In some embodiments, the substituted ring B is R6 (R )p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.

[001497] In some embodiments, A is thiazolyl (eg, 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted by hydroxy (e.g. 2-hydroxy-2-propyl); R2, when present, is C1-C6 alkyl optionally substituted by hydroxyl (e.g., methyl, hydroxymethyl or hydroxyethyl); the substituted ring (Y)q

Nido B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring.

[001498] In some embodiments, A is pyrazolyl (eg, 3-pyrazolyl); m is 1; n is 0; R1 is optionally substituted C1-C6 alkyl (Y)q

N for 1 to 3 halo (e.g. fluoro); substituted ring B is (Z)r;

q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring.

[001499] In some embodiments, A is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted by NR8R9 (e.g. dimethylamino); R2, when present, is halo (e.g., fluoro); the (Y)q

N substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or in whom, when two Y's are present at the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001500] In some embodiments, the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom, or a heteroatomic group selected from N, NH, and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)=N; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each one of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O ) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy , S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with a or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001501] In some embodiments, the optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each one of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O ) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by an o u more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001502] In some embodiments, the optionally substituted ring A is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each one of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both adjacent atoms is/are a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S (O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each one independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S (O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S (O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with a or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001503] In some embodiments, the optionally substituted ring A is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each one independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cyclo-

alkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9 , wherein C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001504] In some embodiments, the optionally substituted ring A is , wherein Rx is selected from the group consisting of H and C1-C6 alkyl (eg, methyl); Z1 is selected from the group consisting of O, NH and -CH2- optionally substituted by 1 to 2 R20; Z2 is selected from the group consisting of NH and -CH2- optionally substituted with 1 to 2 R20; Z3 is selected from the group consisting of -CH2- optionally substituted by 1 to 2 R20, -CH2CH2- optionally substituted by 1 to 2 R20, and -CH2CH2CH2- optionally substituted by 1 to 2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g. fluoro), oxo, C1-C6 alkyl (e.g. methyl or ethyl) optionally substituted by an R21, C1-C6 alkoxy (e.g. , methoxy, ethoxy or isopropoxy) optionally substituted by an R21, NR8R9, 3 to 10 membered heterocycloalkyl (e.g. azetidinyl or pyrrolidinyl) optionally substituted by an R21 or a pair of R20 on the same atom taken together with the atom connecting them independently form a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted by OS(O)2Ph; R21 is selected from the group consisting of halo (eg fluoro), NR8R9, C2-C6 alkynyl (eg ethynyl) and C1-C6 alkoxy (eg methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (eg, methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (eg methyl or t-butyl) and C1-C6 haloalkyl (eg trifluoromethyl).

[001505] In some embodiments, the optionally substituted ring A is , wherein Z4 is selected from the group consisting of -CH2-, -C(O)-, and NH; Z5 is selected from the group consisting of O, NH, N-CH3 and -CH2-.

[001506] In some embodiments, the substituted ring B is (Y)q

N R6 R7 ; R6 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl) and C3-C10 cycloalkyl (eg cyclopropyl); R7 is selected from C1-C6 alkyl (for example methyl, ethyl or isopropyl), C1-C6 haloalkyl (for example trifluoromethyl) and C3-C10 cycloalkyl (for example cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted by one or more C1-C6 alkyl (eg methyl); q is 0, 1 or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y's are bonded to the same carbon, the two Y's are taken together with the atom to which they are bonded to form a cyclopropyl ring.

[001507] In some embodiments of the compound of Formula AA-1, the

(Y)q

N substituted ring B is R6 R7 ; R6 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl) and C3-C10 cycloalkyl (eg cyclopropyl); R7 is selected from C1-C6 alkyl (for example methyl, ethyl or isopropyl), C1-C6 haloalkyl (for example trifluoromethyl) and C3-C10 cycloalkyl (for example cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted by one or more C1-C6 alkyl (eg methyl); q is 0, 1 or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y's are bonded to the same carbon, the two Y's are taken together with the atom to which they are bonded to form a cyclopropyl ring.

[001508] In some embodiments, the optionally substituted ring A is , wherein Rx is selected from the group consisting of H and C1-C6 alkyl (eg, methyl); Z1 is selected from the group consisting of O, NH and -CH2- optionally substituted by 1 to 2 R20; Z2 is selected from the group consisting of NH and -CH2- optionally substituted with 1 to 2 R20; Z3 is selected from the group consisting of -CH2- optionally substituted by 1 to 2 R20, -CH2CH2- optionally substituted by 1 to 2 R20, and -CH2CH2CH2- optionally substituted by 1 to 2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g. fluoro), oxo, C1-C6 alkyl (e.g. methyl or ethyl) optionally substituted by an R21, C1-C6 alkoxy (e.g. , methoxy, ethoxy or isopropoxy) optionally substituted by an R21, NR8R9, 3 to 10 membered heterocycloalkyl (e.g. azetidinyl or pyrrolidinyl) optionally substituted by an R21 or a pair of R20 on the same atom taken together with the atom connecting them independently form a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted by OS(O)2Ph; R21 is selected from the group consisting of halo (eg fluoro), NR8R9, C2-C6 alkynyl (eg ethynyl) and C1-C6 alkoxy (eg methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (eg, methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (eg methyl or t-butyl) and C1-C6 haloalkyl (eg trifluoromethyl); and (Y)q

N substituted ring B is R6 R7 ; R6 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl) and C3-C10 cycloalkyl (eg cyclopropyl); R7 is selected from C1-C6 alkyl (for example methyl, ethyl or isopropyl), C1-C6 haloalkyl (for example trifluoromethyl) and C3-C10 cycloalkyl (for example cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted by one or more C1-C6 alkyl (eg methyl); q is 0, 1 or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y's are bonded to the same carbon, the two Y's are taken together with the atom to which they are bonded to form a cyclopropyl ring.

[001509] In some embodiments, the optionally substituted ring

A is selected from the group consisting of: , , , , , , , , , , , , , , , ,

AT THE N , , , , , , , , , , , , , , , , , ,

, , , , , , , , , , , , , , and ; and the substituted ring B is selected from the group consisting of: , , , , , , , and . [4A]

[001510] In some embodiments, ring A is a 5-membered heteroaryl containing two or more heteroatoms, each independently selected from N, O, and S (e.g., N and S (e.g., ring A is pyrazolyl (e.g. pyrazol-3-yl) or thiazolyl (e.g. thiazol-5-yl)) m is 1, n is 0 or 1;

R1 is C1-C6 (e.g. C2-C4) alkyl optionally substituted by one or more substituents each independently selected from hydroxy and halo; R2 is halo or C1 -C6 alkyl optionally substituted by one or more hydroxy; (Y)q

N the substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001511] In certain embodiments of [4A], the A ring is thiazolyl (eg thiazol-5-yl). In certain such embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted by one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is or . In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy. In certain other embodiments, n is 0.

[001512] In certain embodiments of [4A], the A ring is pyrazolyl. In certain such embodiments, R1 is C1-C6 alkyl optionally substituted by one or more halo (e.g. 0, 1, 2 or 3 (e.g. 0, 2 or 3)). In certain of the foregoing embodiments, R2 is halo (eg, F).

[001513] In certain embodiments of [4A], q is 0; and r is 1 or 2.

[001514] For example, the substituted ring B is selected from:

N , , , and (for

N example, , and ). [4B]

[001515] In some embodiments, ring A is a 5-membered heteroaryl containing two or more (e.g. two) heteroatoms, each independently selected from N, O and S (e.g. N and S (e.g. , ring A is pyrazolyl (e.g. pyrazol-3-yl) or thiazolyl (e.g. thiazol-5-yl)); m is 1; n is 0 or 1; R1 is C1-C6 (e.g. C2 -C4) alkyl optionally substituted by one or more substituents each independently selected from hydroxy and halo; R2 is halo or C1-C6 alkyl optionally substituted by one or more hydroxy; and (Y)q

N(R7)p substituted ring B is; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two

Y are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001516] In certain embodiments of [4B], the A ring is thiazolyl (eg thiazol-5-yl). In certain such embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted by one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is or . In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy. In certain other embodiments, n is 0.

[001517] In certain embodiments of [4B], the A ring is pyrazolyl. In certain such embodiments, R1 is C1-C6 alkyl optionally substituted by one or more halo (e.g. 0, 1, 2 or 3 (e.g. 0, 2 or 3)). In certain of the foregoing embodiments, R2 is halo (eg, F).

[001518] In certain embodiments of [4B], p is 1 or 2.

[001519] In certain of these embodiments, p is 2.

[001520] In certain other embodiments, p is 1; and R7 is selected from C1-C6 alkyl (e.g. methyl, ethyl or isopropyl) and C3-C10 cycloalkyl (e.g. cyclopropyl).

[001521] In certain embodiments of [4B], q is 0.

[001522] In certain embodiments of [4B], the substituted ring B is selected from the group consisting of: , , , ,

CF 3 CF3 CF3

N N N N N , , , , ,

N N N N N , , , and .

[001523] For example, substituted ring B is selected from: CF3 CF3

No

N N , , , , , N N CF3 N N

N , , , , ,

N N e .

[001524] In some embodiments of Formula AA-1, ring A' is the 5-membered heteroaryl containing two or more heteroatoms (e.g., two), each independently selected from N, O, and S (e.g., N and S); m is 1; and n is 0 or 1. In certain such embodiments, ring A' is thiazolyl (eg, thiazol-5-yl) or pyrazolyl (eg, pyrazol-3-yl).

[001525] In certain embodiments (when the A' ring is a 5-membered heteroaryl containing two or more heteroatoms, each independently

pending selected from N, O and S (eg N and S); m is 1; and n is 0 or 1), R1 is C1-C6 (e.g. C2-C4) alkyl optionally substituted by one or more substituents each independently selected from hydroxy, NR8R9 and halo (e.g. hydroxy). In certain of these embodiments, n is 1; and R2 is halo (e.g. F). In certain other embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy.

[001526] In some embodiments of Formula AA-1, ring A' is a 5-membered heteroaryl containing a ring sulfur atom and optionally one or more nitrogen atoms; m is 1; and n is 0 or 1. In certain such embodiments, ring A' is thiophenyl or thiazolyl (e.g., thiazolyl (e.g., thiazol-5-yl)).

[001527] In certain embodiments (when ring A' is a 5-membered heteroaryl containing a ring sulfur atom; m is 1; en is 0 or 1), R1 is C1-C6 alkyl optionally substituted by one or more substituents , each independently selected from hydroxy, NR8R9 and halo (e.g., hydroxy). In certain of these embodiments, n is 1; and R2 is halo (e.g. F). In certain other embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy.

[001528] In some embodiments, the A' ring is thiazolyl (eg, thiazol-5-yl); m is 1; and n is 0 or 1. In certain such embodiments, R1 is C1-C6 alkyl optionally substituted by one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is or . In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy. In certain other embodiments, n is 0.

[001529] In some embodiments, the A' ring is pyrazolyl; m is 1; and n is 0 or 1. In certain of these embodiments, R1 is C1-C6 (e.g., C2-

C4) alkyl optionally substituted by one or more halo (eg 0, 1, 2 or 3 (eg 0, 2 or 3)). In certain of the foregoing modalities, R2 is halo (eg, F).

[001530] In some embodiments of the compound of Formula AA-1, A' is thiazolyl (e.g. 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted by hydroxy (e.g. 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted by hydroxyl (e.g., methyl, hydroxymethyl or hydroxyethyl).

[001531] In some embodiments of the compound of Formula AA-1, A' is pyrazolyl (e.g. 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted by 1 to 3 halo (e.g. fluoro).

[001532] In some embodiments of the compound of Formula AA-1, A' is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted with NR8R9 (e.g. dimethylamino); and R2, when present, is halo (e.g., fluoro).

[001533] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or group heteroatom selected from N, NH, and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)( NHR3)=N; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each one of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heterocyclic

heteroatomic atoms and/or groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O ) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2) C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2) C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more is substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl , C6-C10 aryl and CONR8R9.

[001534] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S (O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each one independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S (O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S (O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with a or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001535] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S (O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each one independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S (O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S (O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with a or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001536] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is, wherein Rx is selected from the group consisting of H and C1-C6 alkyl (eg, methyl); Z1 is selected from the group consisting of O, NH and -CH2- optionally substituted by 1 to 2 R20; Z2 is selected from the group consisting of NH and -CH2- optionally substituted by 1 to 2 R20; Z3 is selected from the group consisting of -CH2- optionally substituted by 1 to 2 R20, -CH2CH2- optionally substituted by 1 to 2 R20, and -CH2CH2CH2- optionally substituted by 1 to 2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g. fluoro), oxo, C1-C6 alkyl (e.g. methyl or ethyl) optionally substituted by an R21, C1-C6 alkoxy (e.g. methoxy , ethoxy or isopropoxy) optionally substituted by an R21, NR8R9, 3 to 10 membered heterocycloalkyl (e.g. azetidinyl or pyrrolidinyl) optionally substituted by an R21 or a pair of R20 on the same atom taken together with the atom connecting them , independently form a C3-C4 monocyclic carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted by OS(O)2Ph; R21 is selected from the group consisting of halo (eg, fluoro), NR8R9, C2-C6 alkynyl (eg, ethynyl), and C1-C6 alkoxy (eg, methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (eg, methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (eg methyl or t-butyl) and C1-C6 haloalkyl (eg trifluoromethyl).

[001537] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is, wherein Z4 is selected from the group consisting of -CH2-, -C(O)-, and NH; Z5 is selected from the group consisting of O, NH, N-CH3 and -CH2-.

[001538] In some embodiments of the compound of Formula AA-1, the (Y)q

N substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are considered together with the carbon to which they are bonded to

to form a cyclopropyl ring.

[001539] In some embodiments of the compound of Formula AA-1, the (Y)q

N(R7)p substituted ring B is ; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001540] In some embodiments of the compound of Formula AA-1, the R6''

N R6''(R7)p substituted ring B is ; each R6'' is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluoro); p is 0 or

1.

[001541] In some embodiments of the compound of Formula AA-1, the R6''

N R6''(R7)p substituted ring B is ; each R6'' is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluoro); p is 0 or

1.

[001542] In some embodiments of the compound of Formula AA-1, A' is thiazolyl (e.g. 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted by hydroxy (e.g.

2-hydroxy-2-propyl); R2, when present, is C1-C6 alkyl optionally substituted by hydroxyl (e.g. methyl, hydroxymethyl or hydro-(Y)q

N-xyethyl); substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring.

[001543] In some embodiments of the compound of Formula AA-1, A' is pyrazolyl (e.g. 3-pyrazolyl); m is 1; n is 0; R1 is C1-C6 alkyl optionally substituted by 1 to 3 halo (e.g. fluoro); the (Y)q

N substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001544] In some embodiments of the compound of Formula AA-1, A' is phenyl; m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted

followed by NR8R9 (e.g. dimethylamino); and R2, when present, is (Y)q

N halo (e.g. fluoro); substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or in whom, when two Y's are present at the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001545] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom, or heteroatomic group selected from N, NH, and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O) (NHR3)=N; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each one of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatom groups.

independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and the carbocyclic ring or the heterocyclic is optionally substituted independently by one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9 , =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein C1 -C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001546] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S (O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and/or R2),

wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, the C3-C10 cycloalkyl, and the 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo , NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001547] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S (O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each one independently selected from hydroxy, halo, oxo, C1-C6 alkyl

la, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, heteroaryl with 5- to 10-membered, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, heteroaryl 5- to 10-membered, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2 -C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001548] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, CO- OC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1 -C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl members are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-

C6 alkyl, C6-C10 aryl and CONR8R9.

[001549] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is, wherein Rx is selected from the group consisting of H and C1-C6 alkyl (eg, methyl); Z1 is selected from the group consisting of O, NH and -CH2- optionally substituted by 1 to 2 R20; Z2 is selected from the group consisting of NH and -CH2- optionally substituted by 1 to 2 R20; Z3 is selected from the group consisting of -CH2- optionally substituted by 1 to 2 R20, -CH2CH2- optionally substituted by 1 to 2 R20, and -CH2CH2CH2- optionally substituted by 1 to 2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g. fluoro), oxo, C1-C6 alkyl (e.g. methyl or ethyl) optionally substituted by an R21, C1-C6 alkoxy (e.g. methoxy , ethoxy or isopropoxy) optionally substituted by an R21, NR8R9, 3 to 10 membered heterocycloalkyl (e.g. azetidinyl or pyrrolidinyl) optionally substituted by an R21 or a pair of R20 on the same atom taken together with the atom connecting them independently form a C3-C4 monocyclic carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted by OS(O)2Ph; R21 is selected from the group consisting of halo (eg, fluoro), NR8R9, C2-C6 alkynyl (eg, ethynyl), and C1-C6 alkoxy (eg, methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (eg, methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (eg methyl or t-butyl) and C1-C6 haloalkyl (eg trifluoromethyl).

[001550] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is, wherein Z4 is selected from the group consisting of -CH2-, -C(O)-, and NH; Z5 is selected from the group consisting of O, NH, N-CH3 and -CH2-.

[001551] In some embodiments of the compound of Formula AA-1, the (Y)q

N substituted ring B is R6 R7 ; R6 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl) and C3-C10 cycloalkyl (eg cyclopropyl); R7 is selected from C1-C6 alkyl (for example methyl, ethyl or isopropyl), C1-C6 haloalkyl (for example trifluoromethyl) and C3-C10 cycloalkyl (for example cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted by one or more C1-C6 alkyl (eg methyl); q is 0, 1 or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y's are bonded to the same carbon, the two Y's are taken together with the atom to which they are bonded to form a cyclopropyl ring.

[001552] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is, wherein Rx is selected from the group consisting of H and C1-C6 alkyl (e.g., methyl); Z1 is selected from the group consisting of O, NH and -CH2- optionally substituted by 1 to 2 R20; Z2 is selected from the group consisting of NH and -CH2- optionally substituted with 1 to 2

R20; Z3 is selected from the group consisting of -CH2- optionally substituted by 1 to 2 R20, -CH2CH2- optionally substituted by 1 to 2 R20, and -CH2CH2CH2- optionally substituted by 1 to 2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g. fluoro), oxo, C1-C6 alkyl (e.g. methyl or ethyl) optionally substituted by an R21, C1-C6 alkoxy (e.g. methoxy , ethoxy or isopropoxy) optionally substituted by an R21, NR8R9, 3 to 10 membered heterocycloalkyl (e.g. azetidinyl or pyrrolidinyl) optionally substituted by an R21 or a pair of R20 on the same atom taken together with the atom connecting them independently form a C3-C4 monocyclic carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted by OS(O)2Ph; R21 is selected from the group consisting of halo (eg, fluoro), NR8R9, C2-C6 alkynyl (eg, ethynyl), and C1-C6 alkoxy (eg, methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (eg, methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (eg methyl or t-butyl) and C1-C6 haloalkyl (eg trifluoromethyl); and (Y)q

N substituted ring B is R6 R7 ; R6 is selected from C1-C6 alkyl (eg methyl); R7 is selected from C1-C6 alkyl (eg isopropyl) and C3-C10 cycloalkyl (eg cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted by one or more C1-C6 alkyl (eg methyl); q is 0, 1 or 2; each Y is independently selected

from among C1-C6 alkyl (e.g. methyl); or, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001553] In some embodiments of the compound of Formula AA-1, the optionally substituted ring A' is selected from the group consisting of: , , , , , , , , , , , , ,

AT THE N , , , , , , , , , , , , , , , , , ,

, , , , , , , , , , , , , , , , , and ; and the substituted ring B is selected from the group consisting of: , , , , , , , and . [4C]

[001554] In some embodiments, the A' ring is a heteroaryl with

5 members containing two or more heteroatoms, each independently selected from N, O and S (e.g. N and S (e.g. ring A' is pyrazolyl (e.g. pyrazol-3-yl) or thiazolyl ( e.g. thiazol-5-yl)); m is 1; n is 0 or 1; R1 is C1-C6 (e.g. C2-C4) alkyl optionally substituted by one or more substituents each independently selected from hydroxy and halo; R2 is halo or C1-C6 alkyl optionally substituted by one or more hydroxy; (Y)q

N the substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001555] In certain embodiments of [4C], the A' ring is thiazolyl (eg thiazol-5-yl). In certain such embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted by one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is or . In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy. In certain other embodiments, n is 0.

[001556] In certain embodiments of [4C], the A' ring is pyrazolyl. In certain such embodiments, R1 is C1-C6 alkyl optionally substituted by one or more halo (e.g. 0, 1, 2 or 3 (e.g. 0, 2 or 3)). In certain of the foregoing embodiments, R2 is halo (eg, F).

[001557] In certain embodiments of [4C], q is 0; and r is 1 or 2.

[001558] For example, the substituted ring B is selected from:

N , , , and (for

N example, , and ). [4D]

[001559] In some embodiments, the A' ring is a 5-membered heteroaryl containing two or more (e.g., two) heteroatoms, each independently selected from N, O, and S (e.g., N and S (e.g., ring A' is pyrazolyl (e.g. pyrazol-3-yl) or thiazolyl (e.g. thiazol-5-yl)); m is 1; n is 0 or 1; R1 is C1-C6 (e.g. , C2-C4) alkyl optionally substituted by one or more substituents each independently selected from hydroxy and halo; R2 is halo or C1-C6 alkyl optionally substituted by one or more hydroxy; and

(Y)q

N(R7)p substituted ring B is; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001560] In certain embodiments of [4D], the A' ring is thiazolyl (eg thiazol-5-yl). In certain such embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted by one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is or . In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted by one or more hydroxy. In certain other embodiments, n is 0.

[001561] In certain embodiments of [4D], the A' ring is pyrazolyl. In certain such embodiments, R1 is C1-C6 alkyl optionally substituted by one or more halo (e.g. 0, 1, 2 or 3 (e.g. 0, 2 or 3)). In certain of the foregoing embodiments, R2 is halo (eg, F).

[001562] In certain modes of [4D], p is 1 or 2.

[001563] In certain of these embodiments, p is 2.

[001564] In certain other embodiments, p is 1; and R7 is selected from C1-C6 alkyl (e.g. methyl, ethyl or isopropyl) and C3-C10 cycloalkyl (e.g. cyclopropyl).

[001565] In certain embodiments of [4D], q is 0.

[001566] In certain embodiments of [4D], the substituted ring B is selected from the group consisting of: , , , , CF 3 CF3 CF3

N N N N N , , , , ,

N N N N N , , , and .

[001567] For example, substituted ring B is selected from: CF3 CF3

No

N N , , , , , N N CF3 N N

N , , , , ,

N N e .

[001568] In some embodiments of the compound of Formula AA-2, A'' is thiophenyl (e.g. 2-thiophenyl); m' is 1; n' is 0; and R1 is C1-C6 al-

alkyl optionally substituted by hydroxyl or oxo (e.g. iso-propyl, 2-hydroxy-2-propyl or 1-propanoyl).

[001569] In some embodiments of the compound of Formula AA-2, the (Y)q

N substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001570] In some embodiments of the compound of Formula AA-2, the (Y)q

N(R7)p substituted ring B is ; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001571] In some embodiments of the compound of Formula AA-2, R6

N R6(R7)p substituted ring B is ; each R6 is independently selected

from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluoro); p is 0 or

1.

[001572] In some embodiments of the compound of Formula AA-2, R6

N 7 substituted ring B is R 6 (R )p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluoro); p is 0 or

1.

[001573] In some embodiments of the compound of Formula AA-2, A'' is thiophenyl (e.g. 2-thiophenyl); m' is 1; n' is 0; R1 is C1-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. isopropyl, 2-hydroxy-2-propyl or 1-propanoyl); the substituted ring B is (Y)q

N(Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when the two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring.

[001574] In some embodiments of the compound of Formula AA-3, A'' is thiophenyl (e.g. 2-thiophenyl); m'' is 1; n'' is 1; R1' is C2-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. 2-hydroxy-2-propyl); and R2' is C2 -C6 alkyl optionally substituted by hydroxyl or oxo (e.g. 2-hydroxy-2-propyl).

[001575] In some embodiments of the compound of Formula AA-3, the (Y)q

N substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001576] In some embodiments of the compound of Formula AA-3, the (Y)q

N(R7)p substituted ring B is ; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001577] In some embodiments of the compound of Formula AA-3, R6

N R6(R7)p substituted ring B is ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is inde-

pending selected from halo (e.g., fluoro); p is 0 or

1.

[001578] In some embodiments of the compound of Formula AA-3, R6

N 7 substituted ring B is R 6 (R )p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluoro); p is 0 or

1.

[001579] In some embodiments of the compound of Formula AA-3, A'' is thiophenyl (e.g. 2-thiophenyl); m'' is 1; n'' is 1; R1' is C2-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. 2-hydroxy-2-propyl); R2' is C2 -C6 alkyl optionally substituted by hydroxyl or oxo (e.g. 2-hydroxy-2-propyl); the substituted ring B is (Y)q

N(Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001580] In some embodiments of the compound of Formula AA-3, the optionally substituted ring A'' is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, considered together with the atoms connecting them, independently form a ring.

C4-C12 monocyclic or bicyclic carbocyclic or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl , C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, CO-OC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl , C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5-10 heteroaryl C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001581] In some embodiments of the compound of Formula AA-3, the (Y)q

N substituted ring B is R6 R7 ; R6 is selected from C1-C6 alkyl (eg methyl); R7 is selected from C1-C6 alkyl (eg isopropyl) and C3-C10 cycloalkyl (eg cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted by one or more C1-C6 alkyl (eg methyl); q is 0, 1 or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or, when two Y's are bonded to the same carbon, the two Y's are considered together.

bond with the carbon to which they are attached to form a cyclopropyl ring.

[001582] In some embodiments, the optionally substituted ring A'' is selected from the group consisting of: and ; and the substituted ring B is selected from the group consisting of: , , , , , , , and .

[001583] In some embodiments of the compound of Formula AA-4, A'' is thiophenyl (e.g. 2-thiophenyl); R1 is C1-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. methyl or 2-hydroxy-2-propyl); and R2'' is methyl.

[001584] In some embodiments of the compound of Formula AA-4, R6

N 7 substituted ring B' is R6 (R )p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluoro); p is 0 or

1.

[001585] In some embodiments of the compound of Formula AA-4, A'' is thiophenyl (e.g. 2-thiophenyl); R1 is C1-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. methyl or 2-

R6

N 7 hydroxy-2-propyl); R2'' is methyl; the substituted ring B' is R6 (R )p ; each R6 is independently selected from C1-C6 alkyl (eg isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.

[001586] In some embodiments of the compound of Formula AA-5, the (Y)q

N substituted ring B'' is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring.

[001587] In some embodiments of the compound of Formula AA-5, the (Y)q

N(R7')p substituted ring B'' is; R7' is selected from unbranched C1-C6 alkyl (eg methyl or ethyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are bonded to the same carbon, the two Y's are taken together with the carbon to which they are bonded to form a cyclic ring.

clopropyl.

[001588] In some embodiments, the optionally substituted ring A is ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently - carefully selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2 )C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, where C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10 , COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001589] In some embodiments, the optionally substituted ring A is ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or independent heteroatomic groups

selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy , halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl , S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1 -C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001590] In some embodiments, the optionally substituted ring

S 1

R A is R2 ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS( O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1- C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl 10 members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, = NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001591] In some embodiments, the optionally substituted ring R2

R1 A is; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS( O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1- C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl 10 members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, = NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001592] In some embodiments, the optionally substituted ring A is ; R1 and R2 on adjacent atoms, considered together

together with the atoms connecting them, independently form a C4-C12 monocyclic or bicyclic carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O , NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with an o u more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001593] In some embodiments, the optionally substituted ring

R1 A is R2 ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9,

=NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-membered heterocycloalkyl 10-membered, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and heterocycloalkyl with 3 to 10 members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 , =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001594] In some embodiments, the optionally substituted ring R2

NH 1

R A is ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS( O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1- C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl 10 members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, = NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001595] In some embodiments, the optionally substituted ring R2 R1

N Ae ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 0 to 2 heteroatoms and /heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the nitrogen atom attached to R1), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with a or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C10 cycloalkyl, 3 to 10 membered heterocycloalkyl, and CONR8R9, in that C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 ci 3- to 10-membered chloroalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001596] In some embodiments, the optionally substituted ring

NH R1 A is R2 ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or independent heteroatomic groups

selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy , halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl , S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1 -C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001597] In some embodiments, the optionally substituted ring

HN 1

R A is R2 ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS( O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1- C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl 10 members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, = NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001598] In some embodiments, the optionally substituted ring R2 R1

N Ae ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 0 to 2 heteroatoms and /heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the nitrogen atom attached to R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1- C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C10 cycloalkyl, 3 to 10 membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C 3- to 10-membered cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001599] In some embodiments, the optionally substituted ring

R2

N R1 A is ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 0 to 2 heteroatoms and /heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the nitrogen atom bound to R2), and in which the carbocyclic ring or the heterocyclyl is optionally substituted independently by one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl , NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, heterocycloalkyl with 3 to 10 members, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001600] In some embodiments, the optionally substituted ring A is ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS( O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1- C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl 10 members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, = NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001601] In some embodiments, the optionally substituted ring R2

S 1

R A is R2 ; a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1- C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, wherein a C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, heteroaryl with 5 to

10 membered, C3-C10 cycloalkyl and 3 to 10 membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001602] In some embodiments, the optionally substituted ring R2

S R1 A is R2 ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS( O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1- C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl 10 members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, = NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001603] In some embodiments, the optionally substituted ring

R2

the 1

R A is R2 ; a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1- C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, wherein a C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl with 3 to 10 members are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1 -C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001604] In some embodiments, the optionally substituted ring R2

R1 A is R2 ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently - carefully selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2 )C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, where C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10 , COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001605] In some embodiments, the optionally substituted ring R2 R1

N 1 A is R ; a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring in that a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2; and b) when one of the adjacent atoms is a nitrogen atom, then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O). )2 (in addition to the aforementioned nitrogen atom attached to R1), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6- C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, where C1-C6 alkyl, C1-C6 alkoxy, S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each one independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9

[001606] In some embodiments, the optionally substituted ring R2

NH R1 A is R2 ; a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1- C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, wherein a C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl with 3 to 10 members are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 al-

alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001607] In some embodiments, the optionally substituted ring R2 R1

N A is R2 ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 0 to 2 heteroatoms and /heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the nitrogen atom attached to R1), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with a or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C10 cycloalkyl, 3 to 10 membered heterocycloalkyl, and CONR8R9, in that C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 ci 3- to 10-membered chloroalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001608] In some embodiments, the optionally substituted ring R1

No. 1

R A is R2 ; R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2) C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl - la, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C10 cycloalkyl and 3 to 10 membered heterocycloalkyl members are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10 , COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001609] In some embodiments, the optionally substituted ring R2

N R1 A is R2 ; a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring in that a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2; and b) when one of the adjacent atoms is a nitrogen atom, then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O). )2 (in addition to the aforementioned nitrogen atom attached to R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6- C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, where C1-C6 alkyl, C1-C6 alkoxy, S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each one independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9

[001610] In some embodiments, the optionally substituted ring R2 R1

N 1 A is R ; a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the nitrogen atom (or atoms) attached to R2), and in that the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl,

3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10-membered heteroaryl, C3-C10 cycloalkyl, and heterocycloalkyl with 3 to 10 members are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1 -C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001611] In some embodiments of the compound of Formula AA, when ring A is phenyl, then R1 and R2 are each independently selected from C3-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, F, I, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl, OCOC6- C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2 , NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1- C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally sub substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 to 7 membered, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl),

NHCO(3- to 7-membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring which includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with a or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl , OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein a C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl 3- to 10-membered yl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo , NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001612] In some embodiments of the compound of Formula AA, when ring A is pyridyl, then R1 and R2 are each independently selected from C3-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, F, I, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl, OCOC6- C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2 , NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl and 3 to 7 membered heterocycloalkyl, wherein the C3-C6 alkyl, the C1-C6 haloalkyl and the 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents , each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl 5 to 10 membered), NHCO(3 to 7 membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl, the 5-10-membered heteroaryl, the NHCOC6-C10 aryl,

NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring which includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with a or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl , OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein a C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl 3- to 10-membered yl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo , NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001613] In some embodiments of the compound of Formula AA, when ring A is phenyl, then R1 and R2 are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy , C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO-C6-C10 aryl, CO(5-10 membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl , OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13 )NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3 to 7 membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 3- to 7-membered heterocycloalkyl are optional ionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 7 membered, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl), NHCOC1-C6 alkyl , NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, considered together with the atoms connecting them, independently form a C4 or C6-C12 monocyclic or bicyclic carbocyclic ring.

cyclic or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, hete - 3 to 10 membered rocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C10 3- to 10-membered cycloalkyl and heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyl inyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; when ring A is pyridyl, then R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1 -C6 alkyl, CO-C6-C10 aryl, CO(5-10 membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl) , OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO (5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2 )C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3- C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents, each independent selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(heterocycloalkyl with 3 to 7 members) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or the heterocyclic ring is optionally independently replaced by a or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1 -C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, in that C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl la with 3 to 10 members are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; and R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl , CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl members, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2- C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1- C6 alkyl, CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 10 membered heterocycloalkyl 7 members), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two independent heteroatoms

carefully selected among oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms. mos and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001614] In some embodiments of the compound of Formula AA-1, when ring A' is phenyl, then R1 and R2 are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1 -C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2 -C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N( C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-( C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cy-

3- to 7-membered cloalkyl and heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently - selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5-10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl to 10-membered), NHCO(3- to 7-membered heterocycloalkyl) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring which includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with a or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-

C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, where C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl , C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; when ring A is pyridyl, then R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1 -C6 alkyl, CO-C6-C10 aryl, CO(5-10 membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl) , OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO (5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2 )C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3- C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents, each independent selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(heterocycloalkyl with 3 to 7 members) and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the 3- to 7-membered R1 or R2 heterocycloalkyl is further optionally substituted independently by one to three hydroxy , halo, NR8R9 or oxo; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or the heterocyclic ring is optionally independently replaced by a or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1 -C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, in that C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and heterocycloalkyl la with 3 to 10 members are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 al-

kyla, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6'' is selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6'' is optionally substituted by one or more substituents independently selected from hydroxy , Cl, Br, I, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10 members), NHCO(3 to 7 membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6'' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6'' is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl;

R7 is selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10 members), NHCO(heterocycloalkyl co m 3 to 7 members), NHCOC2-C6 alkynyl, C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl, or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6'' and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001615] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).

[001616] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).

[001617] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).

[001618] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-

propyl).

[001619] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).

[001620] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).

[001621] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).

[001622] In some embodiments of Formula AA, Ring A is , or (eg ); and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).

[001623] In some forms of Formula AA, Ring A is , ,or ; and R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).

[001624] In some forms of Formula AA, Ring A is

; and R1 is C1-C6 alkyl substituted by one or more (e.g. one) NR8R9.

[001625] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. one) NR8R9.

[001626] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl substituted by one or more (e.g. one) NR8R9.

[001627] In some forms of Formula AA, Ring A is ; R1 is C1-C6 alkyl substituted by one or more (for example, from 1 to 2) hydroxy (for example, 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R2 is halo.

[001628] In some embodiments of Formula AA, Ring A is , , , or (eg ); R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R2 is halo.

[001629] In some embodiments of Formula AA, Ring A is , , , or ; R1 is C1-C6 alkyl substituted by one or more (e.g. 1 to 2) hydroxy (e.g. 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R2 is halo.

[001630] In some forms of Formula AA, Ring A is ; R1 is C1-C6 alkyl substituted by one or more (e.g. one) NR8R9; and R2 is halo.

[001631] In some embodiments of Formula AA, Ring A is , , , or (eg ); R1 is C1-C6 alkyl substituted by one or more (e.g. one) NR8R9; and R2 is halo.

[001632] In some embodiments of Formula AA, Ring A is , , or ; R1 is C1-C6 alkyl substituted by one or more (e.g. one) NR8R9; and R2 is halo.

[001633] In some forms of Formula AA, Ring A is ; and each of R1 and R2 is C1 -C6 alkyl substituted by one or more (e.g., 1 to 2) hydroxy.

[001634] In some forms of Formula AA, Ring A is or ; and each of R1 and R2 is C1 -C6 alkyl substituted by one or more (e.g., 1 to 2) hydroxy.

[001635] In some forms of Formula AA, Ring A is or ; and each of R1 and R2 is C1 -C6 alkyl substituted by one or more (e.g., 1 to 2) hydroxy. In certain such embodiments, R2 is hydroxy methyl.

[001636] In some forms of Formula AA, Ring A is ; and R1 is C1-C6 alkyl optionally substituted by one or more halo (e.g. ethyl or difluoromethyl).

[001637] In some embodiments of Formula AA, Ring A is , , , or (eg ); and R1 is C1-C6 alkyl optionally substituted by one or more halo (e.g. ethyl or difluoromethyl).

[001638] In some forms of Formula AA, Ring A is: or ; and R1 is C1-C6 alkyl optionally substituted by one or more halo (e.g. ethyl or difluoromethyl).

[001639] In some embodiments of Formula AA, Ring A is or (eg ); and R1 and R2 taken together with the atoms connecting them independently form a C4-C12 monocyclic or bicyclic carbocyclic ring (e.g. C5 or C6 carbocyclic ring) or a 5 to 12 membered heterocyclic ring (e.g. with 6 members or with 5 members)

monocyclic or bicyclic containing 1 to 3 (e.g. 1 to 2, e.g. 1) heteroatoms independently selected from O, N and S (e.g. N or O), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g. methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g. methoxy, ethoxy, isopropoxy), OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the heteroaryl 5- to 10-membered, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from and hydroxy, halo (e.g. fluoro), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g. amino, methylamino or dimethylamino ), =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001640] In some forms of Formula AA, Ring A is ; and each of R1 and R2 is C1 -C6 alkyl substituted by one or more (e.g., 1 to 2) hydroxy.

[001641] In some embodiments of Formula AA, Ring A is or (eg ); and each of R1 and R2 is C1 -C6 alkyl substituted by one or more (e.g., 1 to 2) hydroxy.

[001642] In some embodiments of Formula AA, Ring A is or (eg ); and R1 and R2 taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring (for example, C5 or C6 carbocyclic ring) or a heterocyclic ring with 5 to 12-membered monocyclic or bicyclic containing 1 to 3 (e.g. 1 to 2, e.g. 1) heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g. methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g. methoxy, ethoxy, isopropoxy ), OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-membered heterocycloalkyl to 10 members (e.g., azetidinyl or oxetanyl), and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo (e.g., fluoro) , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g. amino, methylamino or dimethylamino), =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

[001643] In some embodiments of Formula AA, the substituted ring B is .

[001644] In certain of these embodiments, the R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or heterocyclic ring with 5 7-membered ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl , C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , , , , or ).

[001645] In certain embodiments (when substituted ring B is selected from: ; and R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 ring (e.g. C4 or C5) carbocyclic or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by a or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1 -C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroary 5 to 10 membered la, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl 5 to 10 membered), NHCO(4 to 6 membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001646] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001647] As a non-limiting example of the foregoing embodiments, the substituted ring B is selected from: , , , , ,

No No N F , , , , , ,

, , , , , , , and .

[001648] In certain embodiments (when substituted ring B is ), an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001649] In certain such embodiments, an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001650] In certain embodiments (when the substituted ring B is ; and an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6 and R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 alkoxy and C3-C7 cycloalkyl.

[001651] As non-limiting examples of the above embodiments, B is: or .

[001652] In some embodiments of Formula AA, the substituted ring B is or .

[001653] In certain of these embodiments, the R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or heterocyclic ring with 5 to 7 members containing

1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , , , , , , , or ).

[001654] In certain embodiments (when the substituted ring B is or ; and R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 ring (e.g., C4 or C5) carbocyclic or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy,

halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(heterocycloalkyl with 4 to 6 members), and NHCOC2-C6 alkynyl.

[001655] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001656] As a non-limiting example of the foregoing embodiments, substituted ring B is selected from: and .

[001657] In certain embodiments (when the substituted ring B is or ), an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy , halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-

C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl members) and NHCOC2-C6 alkynyl.

[001658] In certain such embodiments, an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001659] In certain embodiments (when the substituted ring B is or ; and an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy , halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6 and each R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C3-C7 cycloalkyl.

[001660] As non-limiting examples of the above modalities,

B is: .

[001661] In some embodiments of Formula AA, the substituted ring B is , or .

[001662] In certain of these embodiments, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , or .

[001663] In certain embodiments (when substituted ring B is

, or ); and a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1- C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5 to 10 members, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(heteroaryl with 5 10-membered), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl .

[001664] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001665] As a non-limiting example of the foregoing modalities

res, the substituted ring B is selected from:

No

N , , and (e.g. R7 is cyano or halo (e.g. halo, such as F)).

[001666] In some embodiments of Formula AA-1, the substituted ring B is .

[001667] In certain of these embodiments, R6'' and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or heterocyclic ring with 5 7-membered ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl , C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6" and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C5) carbocyclic ring. For example, substituted ring B is , , , , or ).

[001668] In certain embodiments (when substituted ring B is se-

taught among: ; and R6" and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C4 or C5) carbocyclic ring or heterocyclic ring with 5 to 7 members containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1 -C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9): the remaining R6" is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl , 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl members), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001669] In certain such embodiments, the remaining R6" is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6" is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1 -C6 alkoxy.

[001670] As a non-limiting example of the foregoing embodiments, the substituted ring B is selected from:

, , , , ,

No No

N F , , , , , , , , , , , , , and .

[001671] In certain embodiments (when substituted ring B is ), an R6" is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) ), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001672] In certain such embodiments, an R6" is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6" is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1- C6 alkoxy.

[001673] In certain embodiments (when the substituted ring B is ; and an R6" is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) ), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6'' and R7 are independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl , C1-C6 alkoxy and C3-C7 cycloalkyl.

[001674] As non-limiting examples of the above modalities,

B is: or .

[001675] In some embodiments of Formula AA-1, the substituted ring B is or .

[001676] In certain of these embodiments, R6'' and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or heterocyclic ring with 5 7-membered ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl , C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6" and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C5) carbocyclic ring. For example, substituted ring B is , , , , , , , or ).

[001677] In certain embodiments (when substituted ring B is or ; and R6" and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 ring (e.g. , C4 or C5) carbocyclic or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6" is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl os, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl ), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001678] In certain such embodiments, the remaining R6" is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6" is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1 -C6 alkoxy.

[001679] As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

and .

[001680] In certain embodiments (when substituted ring B is or ), an R6" is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4-6 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001681] In certain such embodiments, an R6" is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6" is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1- C6 alkoxy.

[001682] In certain embodiments (when the substituted ring B is or ; and an R6" is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4-6 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6'' and each R7 are independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C3-C7 cycloalkyl.

[001683] As non-limiting examples of the above embodiments, B is: .

[001684] In some embodiments of Formula AA-1, the substituted ring B is , or .

[001685] In certain of these embodiments, a pair of R6" and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo , C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-

C10 aryl and CONR8R9. For example, R6" and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C5) carbocyclic ring. For example, substituted ring B is , or .

[001686] In certain embodiments (when the substituted ring B is , or ; and a pair of R6'' and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 ring (for (e.g., C4 or C5) carbocyclic or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or plus substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6" is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1 -C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5 to 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl,

NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001687] In certain such embodiments, the remaining R6" is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6" is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1 -C6 alkoxy.

[001688] As a non-limiting example of the foregoing embodiments, the substituted ring B is selected from:

No

N, ,e (e.g. R7 is cyano or halo (e.g. halo, such as F)).

[001689] In some embodiments of Formula AA-2, the substituted ring B is .

[001690] In certain of these embodiments, the R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or heterocyclic ring with 5 7-membered ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl , C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9.

For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , , , , or ).

[001691] In certain embodiments (when substituted ring B is selected from: ; and R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 ring (e.g. C4 or C5) carbocyclic or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by a or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1 -C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl a 5 to 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl,

NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001692] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001693] As a non-limiting example of the foregoing embodiments, the substituted ring B is selected from: , , , , ,

No No

N F , , , , , , , , , , , , and .

[001694] In certain embodiments (when substituted ring B is ), an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001695] In certain such embodiments, an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001696] In certain embodiments (when the substituted ring B is ; and an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6 and R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 alkoxy and C3-C7 cycloalkyl.

[001697] As non-limiting examples of the above embodiments, B is: or .

[001698] In some embodiments of Formula AA-2, the substituted ring B is or .

[001699] In certain of these embodiments, the R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or heterocyclic ring with 5 7-membered ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl , C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , , , , , , or ).

[001700] In certain embodiments (when substituted ring B is or ; and R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 ring (e.g., C4 or C5) carbocyclic or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl s, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl ), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001701] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001702] As a non-limiting example of the foregoing embodiments, substituted ring B is selected from: and .

[001703] In certain embodiments (when the substituted ring B is or ), an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy , halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001704] In certain of these embodiments, an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl

(e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy.

[001705] In certain embodiments (when the substituted ring B is or ; and an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy , halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6 and each R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C3-C7 cycloalkyl.

[001706] As non-limiting examples of the above embodiments, B is: .

[001707] In some embodiments of Formula AA-2, the substituted ring B is , or .

[001708] In certain of these embodiments, a pair of R6 and R7 in atoms

Adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from among O, N and S, wherein the carbocyclic ring or the heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , or .

[001709] In certain embodiments (when the substituted ring B is , or ); and a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1- C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9):

the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-membered heteroaryl 10-membered), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl .

[001710] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001711] As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

No

N , , and (e.g. R7 is cyano or halo (e.g. halo, such as F)).

[001712] In some embodiments of Formula AA-3, the substituted ring B is .

[001713] In certain of these embodiments, R6 and R7 on ad-

adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C4 or C5) carbocyclic ring or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6 -C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , , , , or ).

[001714] In certain embodiments (when substituted ring B is selected from: ; and R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 ring (e.g. C4 or C5) carbocyclic or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by a or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9):

the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-membered heteroaryl 10-membered), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl .

[001715] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001716] As a non-limiting example of the foregoing embodiments, the substituted ring B is selected from: , , , , ,

No No N F , , , , , ,

, , , , , , , and .

[001717] In certain embodiments (when substituted ring B is ), an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001718] In certain such embodiments, an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001719] In certain embodiments (when the substituted ring B is ; and an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6 and R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 alkoxy and C3-C7 cycloalkyl.

[001720] As non-limiting examples of the above embodiments, B is: or .

[001721] In some embodiments of Formula AA-3, the substituted ring B is or .

[001722] In certain of these embodiments, the R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or heterocyclic ring with 5 to 7 members containing

1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , , , , , , or ).

[001723] In certain embodiments (when substituted ring B is or ; and R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 ring (e.g., C4 or C5) carbocyclic or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl s, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl ), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001724] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001725] As a non-limiting example of the foregoing embodiments, substituted ring B is selected from: and .

[001726] In certain embodiments (when substituted ring B is or ), an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy , halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-

C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl members) and NHCOC2-C6 alkynyl.

[001727] In certain such embodiments, an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001728] In certain embodiments (when the substituted ring B is or ; and an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy , halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6 and each R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C3-C7 cycloalkyl.

[001729] As non-limiting examples of the previous modalities,

B is: .

[001730] In some embodiments of Formula AA-3, the substituted ring B is , or .

[001731] In certain of these embodiments, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B is , or .

[001732] In certain embodiments (when substituted ring B is

, or ); and a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1- C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5 to 10 members, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(heteroaryl with 5 to 10 membered), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001733] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001734] As a non-limiting example of the foregoing modalities

res, the substituted ring B is selected from:

No

N , , and (e.g. R7 is cyano or halo (e.g. halo, such as F)).

[001735] In some embodiments of Formula AA-4, the substituted ring B' is or .

[001736] In certain of these embodiments, the R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or heterocyclic ring with 5 7-membered ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl , C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, the substituted ring B' is , , , , , , or ).

[001737] In certain embodiments (when the substituted ring B' is or ; and R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 ring (e.g. , C4 or C5) carbocyclic or 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or heteroaryl with 5 to 10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl os, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl ), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001738] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001739] As a non-limiting example of the foregoing modalities

res, the substituted ring B' is selected from: and .

[001740] In certain embodiments (when the substituted ring B' is or ), an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4-6 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl.

[001741] In certain such embodiments, an R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001742] In certain embodiments (when the substituted ring B' is or ; and an R6 is C6-C10 aryl or heteroaryl with 5 to

10 members, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl ), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl): the remaining R6 and each R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C3-C7 cycloalkyl.

[001743] As non-limiting examples of the above embodiments, B is: .

[001744] In some embodiments of Formula AA-4, the substituted ring B' is , or .

[001745] In certain of these embodiments, a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo,

oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg, C5) carbocyclic ring. For example, substituted ring B' is , or .

[001746] In certain embodiments (when the substituted ring B' is , or ); and a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (e.g. C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1- C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5 to 10 members, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(heteroaryl with 5 to 10 members),

OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001747] In certain such embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6 is 5- to 6-membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1- C6 alkyl and C1-C6 alkoxy.

[001748] As a non-limiting example of the foregoing embodiments, the substituted ring B' is selected from:

No

N , , and (e.g. R7 is cyano or halo (e.g. halo, such as F)).

[001749] In some embodiments of Formula AA-5, the substituted ring B'' is .

[001750] In certain of these embodiments, the R6' and R7' on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g., C4 or C5) carbocyclic ring or a heterocyclic ring with 5 to 7 members containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1 -C6 al-

alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. For example, R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C7 (eg C5) carbocyclic ring. For example, the substituted ring B'' is , , , or ).

[001751] In certain embodiments (when the substituted ring B'' is selected from: ; and R6' and R7' on adjacent atoms, considered together with the atoms connecting them, independently form a C4-C7 (e.g. C4 or C5) carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted. - substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9): R6' remainder is 5- to 10-membered C6-C10 aryl or heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl),

OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001752] In certain such embodiments, the remaining R6' is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl and C1-C6 alkoxy. For example, R6' is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1 -C6 alkyl and C1-C6 alkoxy.

[001753] As a non-limiting example of the above embodiments, the substituted ring B'' is selected from: , , , , ,

No No N F , , , , , , , , , , ,

, , and .

[001754] In certain embodiments (when the substituted ring B'' is ), an R6' is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) 10 membered), NHCO(4 to 6 membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

[001755] In certain such embodiments, an R6' is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6' is 5- to 6-membered heteroaryl (e.g. pyridinyl (e.g. pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1 -C6 alkyl and C1-C6 alkoxy.

[001756] In certain embodiments (when the substituted ring B'' is ; and an R6' is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more substituents).

compounds, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, hetero - 5-10 membered aryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO( 5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl): the remaining R6' and R7' are independently selected from the group consisting of CN, halo, C1-C6 unbranched alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C3-C7 cycloalkyl.

[001757] As non-limiting examples of the above embodiments, B'' is: or .

[001758] In some embodiments, the compound of Formula AA is a compound of Formula BB (Formula BB) wherein X1 is selected from CH, CR1, CR2, N, NH, NR1, NR2 and S; X2 is selected from CH, CR1, CR2, N, NH, NR1, NR2 and S; X3 is selected from CH, CR1, CR2, N, NH, NR1, NR2 and S;

X4 is selected from CH, CR1, CR2, N, NH, NR1, NR2 and S; it is aromatic and neutrally charged; X1, X2, X3 and X4 collectively comprise from 0 to 2 R1 and from 0 to 2 R2, wherein the sum of R1 and R2 is 0 to 3; o is 1 or 2 and p is 1 or 2, wherein the sum of o and p is 3 or 4; and e wherein R1, R2, R6 and R7 are as defined hereinbefore.

[001759] In some modalities of Formula BB, X1 is CR1 or CR2.

[001760] In some modalities of Formula BB, X1 is CH.

[001761] In some modalities of Formula BB, X2 is N.

[001762] In some modalities of Formula BB, X2 is CH.

[001763] In some modalities of Formula BB, X2 is CR1 or CR2.

[001764] In some modalities of Formula BB, X3 is CR1 or CR2.

[001765] In some modalities of Formula BB, X3 is NR1 or NR2.

[001766] In some modalities of Formula BB, X4 is N.

[001767] In some modalities of Formula BB, X4 is S.

[001768] In some embodiments of Formula BB, X1 is CR1, X2 is CR1, X3 is NR2, and X4 is N.

[001769] In some embodiments of Formula BB-1, X1 is CR1, X2 is CH, X3 is NR2, and X4 is N.

[001770] In some embodiments of Formula BB-1, X1 is CH, X2 is CR1, X3 is NR2, and X4 is N.

[001771] In some embodiments of Formula BB, X1 is CR1, X2 is N, X3 is CR2, and X4 is S.

[001772] In some embodiments of Formula BB, X1 is CH, X2 is N, X3 is CR2, and X4 is S.

[001773] In some embodiments of Formula BB, X1 is S, X2 is CR1, X3 is CR2, and X4 is CR1.

[001774] In some embodiments of Formula BB, X1 is S, X2 is CR1, X3 is CH, and X4 is CR2.

[001775] In some embodiments of Formula BB, X1 is CR1, X2 is NR2, X3 is N, and X4 is CR1.

[001776] In some embodiments of Formula BB, R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1-C6 alkyl, C1 -C6 haloalkyl and halo), wherein the C1 -C6 alkyl is optionally substituted by one or more substituents each independently selected from hydroxy or R15 (e.g. hydroxyl); or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic 5- to 12-membered heterocyclic ring, wherein: a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes 1 oxygen atom; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 1 oxygen atom (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and /or R2), and wherein the heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, C1-C6 alkoxy and NR8R9.

[001777] In some embodiments of Formula BB, R1 and R2 are each independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy -2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro and acetyl (e.g. methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-

hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl and fluoro), or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic 6-membered heterocyclic ring, wherein: a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes 1 oxygen atom; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 1 oxygen atom (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and /or R2), and wherein the heterocyclic ring is optionally substituted independently by one or more substituents each independently selected from hydroxy, methoxy and methylamino.

[001778] In some embodiments of Formula BB, R1 and R2 are each independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl , fluoromethyl, difluoromethyl and fluoro.

[001779] In some embodiments of Formula BB, R1 and R2 are each independently selected from ethyl, 1,2-dihydroxy-2-propyl and fluoro.

[001780] In some forms of Formula BB, o is 1 and p is 2.

[001781] In some forms of Formula BB, o is 2 and p is 1.

[001782] In some forms of Formula BB, o is 2 and p is 2.

[001783] In some embodiments of Formula BB, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, CO2C1-C6 alkyl and C3-C10 cycloalkyl, where R6 and R7 are each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, oxo and C1-C6 alkyl.

[001784] In some embodiments of Formula BB, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl and C3-C10 cycloalkyl, where R6 and R7 are, each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, oxo and C1-C6 alkyl.

[001785] In some embodiments of Formula BB, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO2Et and cyclopropyl wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from fluoro and methyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally substituted independently.

by one or more substituents independently selected from hydroxy, oxo and methyl.

[001786] In some embodiments of Formula BB, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more methyl.

[001787] In some embodiments of Formula BB, R6 and R7 are each independently selected from methyl and trifluoromethyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more methyl.

[001788] In some embodiments, the compound of Formula AA is a compound of Formula BB-1 (Formula BB-1) wherein J1 and J2 are each independently selected from the group consisting of -CH2-, , - CHR-, -C(=O)- and -CR2-; each R is independently selected from hydroxy and C1 -C6 alkyl; o is 0 or 1 and p is 0 or 1, wherein the sum of o and p is 1 or 2;

X1 is selected from CH and CR1; and X2, X3, X4, R6, and R7 are as defined hereinbefore.

[001789] In some forms of Formula BB-1, X1 is CH.

[001790] In some forms of Formula BB-1, X1 is CR1.

[001791] In some forms of Formula BB-1, X2 is N.

[001792] In some forms of Formula BB-1, X2 is CH.

[001793] In some forms of Formula BB-1, X2 is CR1 or CR2.

[001794] In some forms of Formula BB-1, X3 is CR1 or CR2.

[001795] In some modalities of Formula BB-1, X3 is NR1 or NR2.

[001796] In some forms of Formula BB-1, X4 is N.

[001797] In some modalities of Formula BB-1, X4 is S.

[001798] In some embodiments of Formula BB-1, X1 is CR1, X2 is CR1, X3 is NR2, and X4 is N.

[001799] In some embodiments of Formula BB-1, X1 is CR1, X2 is CH, X3 is NR2, and X4 is N.

[001800] In some embodiments of Formula BB-1, X1 is CH, X2 is CR1, X3 is NR2, and X4 is N.

[001801] In some forms of Formula BB, X1 is CR1, X2 is N, X3 is CR2, and X4 is S.

[001802] In some embodiments of Formula BB-1, X1 is CH, X2 is N, X3 is CR2, and X4 is S.

[001803] In some embodiments of Formula BB-1, X1 is S, X2 is CR1, X3 is CR2, and X4 is CR1.

[001804] In some embodiments of Formula BB, X1 is S, X2 is CR1, X3 is CH, and X4 is CR2.

[001805] In some modalities of Formula BB-1, X1 is CR1, X2 is

NR2, X3 is N, and X4 is CR1.

[001806] In some embodiments of Formula BB-1, R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1-C6 alkyl, C1-C6 haloalkyl and halo), wherein the C1-C6 alkyl is optionally substituted by one or more substituents each independently selected from hydroxyl or R15 (e.g. hydroxyl); or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic 5- to 12-membered heterocyclic ring, wherein: a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes 1 oxygen atom; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 1 oxygen atom (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and /or R2), and wherein the heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, C1-C6 alkoxy and NR8R9.

[001807] In some embodiments of Formula BB-1, R1 and R2 are each independently selected from methyl, ethyl, iso-propyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy -2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro and acetyl (e.g. methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl and fluoro), or a pair of R1 and R2 in adjacent atoms, considered together with the atoms that connect them, independently-

form at least one monocyclic 6-membered heterocyclic ring, wherein: a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes 1 oxygen atom; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 1 oxygen atom (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and /or R2), and wherein the heterocyclic ring is optionally substituted independently by one or more substituents each independently selected from hydroxy, methoxy and methylamino.

[001808] In some embodiments of Formula BB-1, R1 and R2 are each independently selected from methyl, ethyl, iso-propyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl , fluoromethyl, difluoromethyl and fluoro.

[001809] In some embodiments of Formula BB-1, R1 and R2 are each independently selected from ethyl, 1,2-dihydroxy-2-propyl and fluoro.

[001810] In some forms of Formula BB-1, o is 1 and p is 0.

[001811] In some forms of Formula BB-1, o is 0 and p is 1.

[001812] In some forms of Formula BB-1, o is 1 and p is 1.

[001813] In some embodiments of Formula BB-1, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, CO2C1-C6 alkyl and C3-C10 cycloalkyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring,

wherein the carbocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, oxo and C1-C6 alkyl.

[001814] In some embodiments of Formula BB-1, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl and C3-C10 cycloalkyl, wherein R6 and R7 are, each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, oxo and C1-C6 alkyl.

[001815] In some embodiments of Formula BB-1, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO2Et and cyclopropyl, in that R6 and R7 are each optionally substituted by one or more substituents independently selected from fluoro and methyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally substituted independently by one or more independently selected substituents among hydroxy, oxo and methyl.

[001816] In some embodiments of Formula BB-1, R6 and R7 are each independently selected from methyl, ethyl, iso-

propyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more methyl.

[001817] In some embodiments of Formula BB-1, R6 and R7 are each independently selected from methyl and trifluoromethyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more methyl.

[001818] In some embodiments of Formula BB-1, J1 is selected from the group consisting of -CH2-, , -CHR-, -C(=O)- and -CR2; and J2 is -CH2-. In any of these embodiments, R is C1-C6 alkyl (e.g., methyl).

[001819] In some embodiments of Formula BB-1, J1 is selected from the group consisting of -CH2- and -CR2-; and J2 is -CH2-. In any of these embodiments, R is C1-C6 alkyl (e.g., methyl).

[001820] In some embodiments of Formula BB-1, R is C1-C6 alkyl (eg methyl).

[001821] In certain embodiments, J1 is -CH2-; and J2 is -CH2-.

[001822] In some embodiments, the compound of Formula BB is a compound of Formula BB-1a or Formula BB-1b

(Formula BB-1a)

(Formula BB-1a) J1, J2 and J3 are each independently selected from the group consisting of -CH2-, , -CHR-, -CR2- and C(=O); each R is independently selected from hydroxy and C1 -C6 alkyl; X1 is selected from CH and CR1; X2 is selected from N, CH, CR1 and CR2; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1- C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl , wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl ), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or the C1-C6 alkoxy by which R6 or

R7 is substituted is optionally substituted by one or more of hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a carbocyclic ring or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl.

[001823] In some forms of Formula BB-1a, X2 is N.

[001824] In some embodiments of Formula BB-1a, X2 is CH.

[001825] In some forms of Formula BB-1a, X2 is CR1 or CR2.

[001826] In some forms of Formula BB-1b, X1 is selected from CH.

[001827] In some modalities of Formula BB-1b, X1 is selected from CR1.

[001828] In some embodiments of Formula BB-1a and/or Formula BB-1b, each R1 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1- C6 alkyl, C1-C6 haloalkyl and halo), wherein the C1-C6 alkyl is optionally substituted by one or more substituents each independently selected from hydroxyl or R15 (e.g. hydroxyl).

[001829] In some embodiments of Formula BB-1a and/or Formula BB-1b, each R1 is independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy - 2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoro-

romethyl, fluoro, and acetyl (e.g., methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2, 3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl and fluoro).

[001830] In some embodiments of Formula BB-1a and/or Formula BB-1b, each R1 is independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl , fluoromethyl, difluoromethyl and fluoro.

[001831] In some embodiments of Formula BB-1a and/or Formula BB-1b, each R1 is independently selected from ethyl, 1,2-dihydroxy-2-propyl and fluoro.

[001832] In some embodiments of Formula BB-1a, the carbon-connected R1 is halo; X2 is CH; and the nitrogen-linked R1 is C1-C3 alkyl. For example, carbon-linked R1 is fluoro; X2 is CH; and the nitrogen-linked R1 is ethyl.

[001833] In some embodiments of Formula BB-1b, X1 is CH; and R1 is C1-C3 alkyl optionally substituted by one or more hydroxyl. For example, X1 is CH; and R1 is 1,2-dihydroxy-2-propyl.

[001834] In some embodiments of any of the foregoing embodiments, the 1,2-dihydroxy-2-propyl has an (R) configuration at position 2. In other embodiments of any of the foregoing embodiments, the 1, 2-dihydroxy-2-propyl has an (S) configuration in the 2-position.

[001835] In some embodiments of Formula BB-1a and/or Formula BB-1b, each R2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1- C6 alkyl, C1-C6 haloalkyl and halo), wherein the C1-C6 alkyl is optionally substituted by one or more substituents each independently selected from hydroxyl or R15 (e.g. hydroxyl).

[001836] In some embodiments of Formula BB-1a and/or Formula BB-1b, each R2 is independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy - 2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro, and acetyl (e.g. methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1 ,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl and fluoro).

[001837] In some embodiments of Formula BB-1a and/or Formula BB-1b, each R2 is independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl , fluoromethyl, difluoromethyl and fluoro.

[001838] In some embodiments of Formula BB-1a and/or Formula BB-1b, each R2 is independently selected from ethyl, 1,2-dihydroxy-2-propyl and fluoro.

[001839] In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, CO2C1-C6 alkyl and C3-C10 cycloalkyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkyl.

[001840] In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl and C3-C10 cycloalkyl, wherein R6 and R7 are, each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkyl. In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO2Et and cyclopropyl,

wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from fluoro and methyl.

[001841] In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from methyl, ethyl, iso-propyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl.

[001842] In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from methyl and trifluoromethyl. For example, R6 is methyl; and R7 is trifluoromethyl.

[001843] In some embodiments of Formula BB-1a, J1 and J2 are independently selected from -CH2-, -CHR- and -CR2-.

[001844] In some embodiments of Formula BB-1a, J1 is selected from -CH2-, -CHR- and -CR2-; and J2 is -CH2-.

[001845] In some embodiments of Formula BB-1a, J1 is selected from -CH2- and -CR2-; and J2 is -CH2-.

[001846] In some embodiments of Formula BB-1b, J1 and J3 are independently selected from the group consisting of -CH2-, , -CHR-, -CR2- and -C(=O)-. In either of these embodiments, R is C1-C6 alkyl (eg, methyl).

[001847] In some embodiments of Formula BB-1b, J1 and J3 are independently selected from the group consisting of -CH2- and -CR2-.

[001848] In some modalities of Formula BB-1b, one or two of J1 and J3 are different from CH2.

[001849] In some embodiments of Formula BB-1b, J1 is -CHR-, -CR2- or -C(=O)- (e.g., -CHR-, -CR2-); and J3 is CH2.

[001850] In some modalities of Formula BB-1a and/or Formula

BB-1b, R is C1-C6 alkyl (e.g. methyl).

[001851] In some embodiments, the compound of Formula BB is a compound of Formula BB-1a.

[001852] In some embodiments, the compound of Formula BB is a compound of Formula BB-1b.

[001853] In some embodiments, the compound of Formula BB is a compound of Formula BB-1a-i or Formula BB-1b-i (Formula BB-1a-i) (Formula BB-1a-i) J1 is selected from the group consisting of -CH2-, -CHR-, -CR2- and -C(=O)-; each R is independently selected from hydroxy and C1 -C6 alkyl; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1- C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl , wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl ), C6-C10 aryloxy, and S(O2)C1-

C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more of hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl.

[001854] In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R1 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo and C(O)R13 (e.g. , C1-C6 alkyl, C1-C6 haloalkyl and halo) wherein the C1-C6 alkyl is optionally substituted by one or more substituents each independently selected from hydroxyl or R15 (e.g. hydroxyl).

[001855] In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R1 is independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2- propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro, and acetyl (e.g., methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl and fluoro).

[001856] In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R1 is independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2- hydroxy-2-propyl, fluoromethyl,

difluoromethyl and fluoro.

[001857] In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R1 is independently selected from ethyl, 1,2-dihydroxy-2-propyl and fluoro.

[001858] In some embodiments of Formula BB-1a-i, the carbon-connected R1 is halo; and the nitrogen-linked R1 is C1-C3 alkyl.

[001859] In some embodiments of Formula BB-1b-i, R1 is C1-C3 alkyl optionally substituted by one or more hydroxyl.

[001860] In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, CO2C1-C6 alkyl and C3-C10 cycloalkyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkyl.

[001861] In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl and C3-C10 cycloalkyl, wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkyl.

[001862] In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO2Et and cyclopropyl , wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from fluoro and methyl.

[001863] In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl,

wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from fluoro and methyl.

[001864] In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from methyl, ethyl, iso-propyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl.

[001865] In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from methyl and trifluoromethyl.

[001866] In some embodiments of Formula BB-1b, J1 is selected from the group consisting of , -CHR- and -CR2-.

[001867] In some embodiments of Formula BB-1b, J1 is selected from the group consisting of -CHR- and -CR2-.

[001868] In some embodiments, the compound of Formula BB is a compound of Formula BB-1a-i.

[001869] In some embodiments, the compound of Formula BB is a compound of Formula BB-1b-i. Additional Characteristics of the Modalities In This Document

[001870] In some embodiments of the compound of Formula AA (e.g., Formula AA-1, Formula AA-2, Formula AA-3, Formula AA-4 or Formula AA-5), R6 is not CN.

[001871] In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of: , ,

, ,

H H H2N N

HN N N N O S N Y Y N O O The O HO

HO F , , H2N

H H2N H

N N N s No O N S Y N The O The O HO

HO , F , and .

[001872] In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of: , ,

HN H N N Y Y N The O HO , F ,

H H2N N H2N

H N N N O S N S The No. O O O O

HO HO , and H2N H

N N Y Y N The O HOF

[001873] In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:

H H H2N H2N N

H N N N HN N O S N O S N No Y Y N O O O O The O HO HO

HO F , , , H2N H

N N Y Y N The O

HOF, e.g.

[001874] In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:

H H H2N N

HN N N N O S N Y Y N O O The O HO

HO F , , H2N

H H2N H

N N N s No O N S Y N The O The O HO

HO and F.

[001875] In some embodiments, the compound of any of the formulas herein is not a compound disclosed in Provisional Application No. US 62/536,271, filed July 24, 2017; and in Provisional Application No. US 62/573,894, filed October 18, 2017, each of which are incorporated herein by reference in their entirety.

[001876] In some embodiments, the compound of any of the formulas herein is not a compound disclosed in EP 0173498, which is incorporated herein by reference in its entirety.

[001877] In some embodiments, the compound of any of the formulas herein is not a compound disclosed in US 4666506, which is incorporated herein by reference in its entirety.

[001878] In one embodiment, there is provided herein a combination of a compound of any above modality, for use in treating or preventing a TNF-α-mediated condition, in a patient in need thereof, wherein the compound is administered to said patient in a therapeutically effective amount. Preferably, the subject is resistant to treatment with an anti-TNFα agent. Preferably, the condition is an intestinal disease or disorder.

[001879] In one embodiment, there is provided herein a pharmaceutical composition comprising a compound of any of the foregoing embodiments and an anti-TNFα agent disclosed herein. Preferably, where the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably, where the anti-TNFα agent is Adalimumab.

[001880] In one embodiment, a pharmaceutical combination of a compound of any modality is provided herein.

prior age and an anti-TNFα agent. Preferably, where the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably, where the anti-TNFα agent is Adalimumab.

[001881] In one embodiment, the present invention relates to an NLRP3 antagonist for use in treating or preventing a TNF-α-mediated condition, in particular a disease or disorder of the gastrointestinal tract, in a patient who need the same, wherein the NLRP3 antagonist is administered to said patient in a therapeutically effective amount.

[001882] In one embodiment, the present invention relates to an NLRP3 antagonist for use in treating or preventing a condition, in particular a disease or disorder of the gastrointestinal tract, in a patient in need thereof, in that the NLRP3 antagonist is administered to said patient in a therapeutically effective amount.

[001883] In one embodiment, the present invention relates to an NLRP3 antagonist for use in treating, stabilizing, or decreasing the severity or progression of a disease or disorder of the gastrointestinal tract, in a patient in need thereof, in that the NLRP3 antagonist is administered to said patient in a therapeutically effective amount.

[001884] In one embodiment, the present invention relates to an NLRP3 antagonist for use in slowing, arresting, or reducing the development of a disease or disorder of the gastrointestinal tract, in a patient in need thereof, in that the NLRP3 antagonist is administered to said patient in a therapeutically effective amount.

[001885] In one embodiment, the present invention relates to an NLRP3 antagonist for use in accordance with the embodiments listed.

of the above, wherein the NLRP3 antagonist is an NLRP3 antagonist that targets the gastrointestinal tract.

[001886] In one embodiment, the present invention relates to an NLRP3 antagonist for use according to any of the above embodiments, wherein the disease of the gastrointestinal tract is IBD.

[001887] In one embodiment, the present invention relates to an NLRP3 antagonist for use according to any of the above embodiments, wherein the gastrointestinal tract disease is US or CD.

[001888] In one embodiment, the present invention relates to a method for treating or preventing a TNF-α-mediated condition, in particular a disease or disorder of the gastrointestinal tract, in a patient in need thereof. , which comprises administering to said patient a therapeutically effective amount of an NLRP3 antagonist that targets the gastrointestinal tract.

[001889] In one embodiment, the present invention relates to a method for treating or preventing a condition, in particular a disease or disorder of the gastrointestinal tract, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an NLRP3 antagonist that targets the gastrointestinal tract.

[001890] In one embodiment, the present invention relates to a method for treating, stabilizing, or lessening the severity or progression of a disease or disorder of the gastrointestinal tract, in a patient in need thereof, which comprises administering to said patient a therapeutically effective amount of an NLRP3 antagonist that targets the gastrointestinal tract.

[001891] In one embodiment, the present invention relates to a method for slowing, stopping, or reducing the development of a disease or disorder of the gastrointestinal tract, in a patient who is

The subject matter thereof comprises administering to said patient a therapeutically effective amount of an NLRP3 antagonist that targets the gastrointestinal tract.

[001892] In one embodiment, the present invention relates to a method according to any one of the above embodiments, wherein the disease of the gastrointestinal tract is IBD.

[001893] In one embodiment, the present invention relates to a method according to any one of the above embodiments x to xx, wherein the disease of the gastrointestinal tract is UC or CD.

[001894] In one embodiment, the present invention relates to a method for treating or preventing a TNF-α-mediated condition, in particular a disease or disorder of the gastrointestinal tract, in a patient in need thereof. , which comprises administering to said patient a therapeutically effective amount of an NLRP3 antagonist that targets the gastrointestinal tract.

[001895] Unless otherwise noted, when a disclosed compound is named and represented by a structure without specifying stereochemistry and has one or more chiral centers, it extends to represent all possible stereoisomers of the compound.

[001896] It is understood that the combination of variables in the formulas herein is such that the compounds are stable.

[001897] In some embodiments, a compound is provided herein that is selected from the group consisting of the compounds in Table 1A:

Table 1A.

Composite Structure post Structure no no

101 141ba

101a 141bb

101b 142

102 142a

Composite Structure post Structure no no

102a 142b

102b 143

103 143a

103aa 143b

Composite Structure post Structure no no

103ab 144

103b 145

103bb 145a

104 145b

Composite Structure post Structure no no

104 to 146

104b 147

105 147a

105a 147b

Composite Structure post Structure no no

105b 148

106 148a

106a 148b

106b 149

Com- Compound Structure post Structure no no

107 149a

107a 149b

107b 150

110 150a

Com- Compound Structure post Structure no no

111 150b

112 151

113 152

114 153

Com- Compound Structure post Structure no no

114a 153a

114b 153b

115 154

116 154a

116a 154b

Com- Compound Structure post Structure no no

116b 155

117 155a

117a 155b

117b 156

Com- Compound Structure post Structure no no

118 156a

118a 156b

118b 157

119 157a

Com- Compound Structure post Structure no no

119a 157b

119b 158

120 158a

120a 158b

Com- Compound Structure post Structure no no

120b 159

121 159a

121a 159b

121b 160

Com- Compound Structure post Structure no no

122 160a

122a 160b

122b 161

123 161a

Com- Compound Structure post Structure no no

124 161b

124 to 162

124b 162aa

125 162ab

125a 162ba

Com- Compound Structure post Structure no no

125b 162bb

(R,R)

126 163

126a 163a

126b 163b

127 164

Compound Structure post Structure no no NH2 O

THE s

N NH 127a 164a

s

HO N 127b 164b 128 165 128a 165a 128b 165b

Composite Structure post Structure No. 129 166

the NH2

S S O

N 129aa 167 HO N HN N 129ab 167a 129ba 167b 129bb 168

Com- Compound Structure post Structure no no

130 168a

130a 168aa

130b 168ab

131 168b

131a 168ba

Com- Compound Structure post Structure no no

131aa 168bb b

131b 169a

131c 169b

131d 170

131 and 171

131f 172

Composite Structure post Structure no no

131g 172a

132 172b

132 to 173

132b 173a

133 173b

Com- Compound Structure post Structure no no

133 to 174

133b 174a

134 174b

134a to 175

134ab 175a

Com- Compound Structure post Structure no no

134b 175b

134bb 176

135 177

136 178

136 to 179

Com- Compound Structure post Structure no no

136b 180

137 180a

137a 180b

137b 181

138 182

Composite Structure post Structure no no

The NH2 F

ONLY

N N 139 183 Y HN N

HO 140 183a 140a 183b 140aa 183c H2N * O * F

ONLY

N N 140ab 183d Y HN N

oh

Com- Compound Structure post Structure no no

140b 184a

140b 184b

140bb 184c

141 184d

141 to 201

141a to 201a

Compound Structure Posted Structure No. 141ab 141b 141ba and pharmaceutically acceptable salts thereof.

[001898] In some embodiments, a compound is provided herein which is selected from the following: 185b 185 185a and pharmaceutically acceptable salts thereof.

[001899] In some embodiments, a compound is provided herein which is selected from the group consisting of the compounds in Table 1B: Table 1B.

301 421

THE AT THE

N H N O 304 N 424 H

N N N N N Y N

O S H2N O O H2N O 305 425 306 426 307 427

MeHN

N O 324 N H 443

No No No s

The H2N The MeHN

N O 325 N H 444

No No No s

The H2N O

Me2N

N O 330 N H 449

No No No s

The H2N The Me2N

N O 331 N H 450

No No No s

The H2N O

ome

No. 351 470 H

N N N N s

O O H2N 352 471 353 472 354 473

MeO

N O 359 478 N H

No N N s

O O H2N 360 479

H O No

N H 386 505 N

N N N s

O O H2N 387 506 388 507 389 508 390 509

N 393 N O 512

N H No N N s

O O H2N 394 513 395 514

H N Boc 405 N O 524

N H No N N s

O O H2N

MeO 415 O 534

No N H No N N s

O O H2N 416 535 and pharmaceutically acceptable salts thereof.

[001900] In some embodiments, a compound is provided herein that is selected from the group consisting of the compounds in Table 1C:

Table 1C

115 to 660

115b 660a

140c 660b

170a 660c

170b 660d

171 to 661

171b 661a

171c 661b

171d 662

176a 662a

176b 662b

H

O N H2N 181a HO S

No

N 662c

THE

S 181b 662d 182a 662e 182b 663 201b 663a 201c 663b

201d 664

201e 664a

201f 664b

304 to 665

304b 667

306a 667a

306b 667b

601 668

601a 668a

601b 668b

602 668c

602a 668d

602b 669

603 669a

604 669b

604 to 670

604b 670a

605 670b

605 to 671

605b 671a

605c 671b

605d 671c

605e 671d

605f 672

605g 673

605h 673a

607 673b

607 to 674

607b 674a

608 674b

608 to 675

608b 675a

608c 675b

608d 676

609 676a

610 676b

610 to 677 CF3

N HN N 610b N 678

S S O

OH O H2N 611 678a 611a 678b 611b 679

612a 680a

612b 680b

613 681

613a 681a

613b 681b

614a 682a 614b 682b 615 683 H2N

THE THE s No

N N 615a N N

H 683a

HO H2N

THE THE s No

N N 615b N N 683b

H HO

616a 684a

616b 684b

617 685

617a 685a

617b 685b

618a 686a

618b 686b

619 687

620 687a

620a 687b

620b 688

621 688a

621a 688b

621b 689

622 689a

622a 689b

622b 690

623 690a

623a 690b

623b 691

624 691a

624a 691b

624b 692

625 692a

625a 692b 625b 693 626 694

HO

HN N 626a N 694a

No S S O

The H2N 626b 694b

628 695a

628a 695b

628b 696

629 697a

630 697b

630a 698a

630b 698b

631 699a

631a 699b

631b 699c

(R) abs

N 632 700a HN

N N N S O

O H 2N 632a 700b 632b 701a 633 701b 633a 702

633b 703

634 704

634a 705a

634b 705b

635 706

636 to 707

636b 708

636c 709

637 710

637 to 711

637b 712

638 713

638a 716a

638b 716b

639 717

639a 718a

639b 719

640 720a

640a 720b

640b 720c

640c 721a

641 721b

642 721c

642 to 722

642b 723a

643 723b

643a 723c

643b 724

644 725a

644 to 726

644b 726a

645 726b

645 to 727

645b 727a

646a 727b

647 728

647a 728a

647b 728b

648 729

648a 729a

648b 729b

649a 730a

649b 730b

650 731

650a 731a

650b 731b

651 732a

651 to 733

651b 734

652 735

652 to 736

652b 737

653 to 739

653b 739a

654 739b

654a 739c

654b 739d

655a 740a

655b 740b

656 741

656a 741a

656b 741b

656c 742

656d 742a

657 742b

657 to 743

657b 743a

658 743b

658a 743c

658b 743d

659 744

659a 744a

659b 744b

744c

744d and pharmaceutically acceptable salts thereof.

[001901] In some embodiments, the compound is selected from the group consisting of compounds in Table 1D below: Table 1D Cmpd Cmpd Structure Structure No. 801 821a 801a 821b 801b 822 802 822a

Cmpd Cmpd Structure Structure No.

802a 822b

802b 823

802c 823a

802d 823b

803 824

Cmpd Cmpd Structure Structure No.

HONO

H 803a Y *N

S N 824a H2N O O N

HONO

H 803b Y * N

Y N 824b H2N O O N 804 825 804a 825a 804b 825b 805 826

Cmpd Cmpd Structure Structure No.

805a 826a

805b 826b

806 827

806a 827a

806b 827b

807 828

Cmpd Cmpd Structure Structure No.

No No F

N H 807a 828a *Y N N

HN * O H N O 2 O N

No No F

N H 807b 828b *S

N N

HN * O H N O 2 O N

No No F

N H 808 828c *

s N N

HN * O H N O 2 O N

No No F

N H 808a 828d *

s N N

HN * O H N O 2 O N 808b 829 809 829a

Cmpd Cmpd Structure Structure No.

809a 829b

809b 829c

810 829d

811 to 830

811b 830a

811 830b

Cmpd Cmpd Structure Structure No.

811 to 831

811b 831a

812 831b

812 to 832

812b 832a

813 832b

Cmpd Cmpd Structure Structure No.

813 to 833

813b 833a

814 833b

814 to 834

814b 834a

814c 834b

814d 835

815 835a

Cmpd Cmpd Structure Structure No.

815a 835b

815d 836

816 836a

816a 836b

816b 837

816c 837a

816d 837b

Cmpd Cmpd Structure Structure No. 817 838 817a 838a

H No

H 817b 838b O *S N N H2N O O N 817c 839 817d 839a 818 839b

Cmpd Cmpd Structure Structure No.

818 to 840

818b 840a

819 840b

819 to 841

819b 841a

820 841b

Cmpd Cmpd Structure Structure No. 820a 842 820b 842a 820c 842b

F

N N 820d * H F 843 S *S

N N H2N O O N 821 843a 843b and pharmaceutically acceptable salts thereof.

[001902] In some embodiments, the compound is selected from the group consisting of compounds in Table 1E below:

Table 1E Cmpd Cmpd Structure Structure No.

901 967b

901 to 968

901b 969

902 969a

Cmpd Cmpd Structure Structure No.

902a 969b

902b 970

903 970a

903a 970b

Cmpd Cmpd Structure Structure No.

903b 971

904 971a

904a 971b

904b 972

Cmpd Cmpd Structure Structure No.

905 973

905 to 974

905b 974a

906 974b

Cmpd Cmpd Structure Structure No.

907 975

907a 975a

907b 975b

908 976

Cmpd Cmpd Structure Structure No.

908a 976a

909 976b

910 977

911 977a

911a 977b

Cmpd Cmpd Structure Structure No.

911b 978

912 978a

912a 978b

912b 979

Cmpd Cmpd Structure Structure No.

913 979a

914 979b

914 to 980

914b 980a

Cmpd Cmpd Structure Structure No.

915 980b

915a 981a

915b 981b

916 981c

916a 982a

Cmpd Cmpd Structure Structure No.

916b 983

917 983a

917a 983b

917b 984

918 984a

918a 984b

Cmpd Cmpd Structure Structure No.

918b 985

919 985a

920 985b

920 to 986

920b 987

921 987a

Cmpd Cmpd Structure Structure No. 921a 987b 921b 988 922 989

F H

N N 922a F N N 990

No s

The H2N O

F H

N N 922b F N N 991

No s

O H2N O 923 992 923a 992a

Cmpd Cmpd Structure Structure No. 923b 993 924 994 924a 994a 924b 995 925 996 CF3

S HN N 926 997 N

HO S O CF3

The H2N 926a 998

Cmpd Cmpd Structure Structure No.

926b 998a

927 999

928 999a

929 1000

930 1000a

931 1001

Cmpd Cmpd Structure Structure No.

932 1001a

933 to 1002

934a 1002a

934b 1003

935a 1003a

935b 1004

935c 1004a

Cmpd Cmpd Structure Structure No.

935d 1005

935e 1005a

936 to 1006

936b 1006a

936c 1007

937a 1007a

937b 1008

Cmpd Cmpd Structure Structure No. 937c 1008a 937d 1009 937e 1009a F3C

F

HN N 937f 1010 N N

N S O

The H2N 938a 1010a 938b 1011 938c 1011a

Cmpd Cmpd Structure Structure No.

939 to 1012

939b 1013

940a 1013a

940b 1014

941a 1014a

941b 1015

941c 1015a

Cmpd Cmpd Structure Structure No.

941d 1016

942a 1016a

942b 1017

942c 1017a

943 to 1018

943b 1018a

944 to 1019

Cmpd Cmpd Structure Structure No.

944b 1019a

945 to 1020

945b 1020a

946 to 1021

946b 1022

947a 1022a

947b 1023

Cmpd Cmpd Structure Structure No.

948 to 1024

948b 1025

949a 1025a

950 to 1026

951a 1026a

952 to 1027

953 to 1028

Cmpd Cmpd Structure Structure No.

954 to 1029

955a 1029a

956 to 1030

957 to 1031

958 to 1032

959 to 1033

Cmpd Cmpd Structure Structure No.

960 to 1034

961a 1034a

962 to 1035

963 to 1036

964 to 1037

965 to 1038

966 to 1039

Cmpd Cmpd Structure Structure No. 967a 1040 1041a 1041 and pharmaceutically acceptable salts thereof.

[001903] In some embodiments, the compound is selected from the group consisting of compounds in Table 1F below: Table 1F Comp. Structure Comp. Structure No. 1100 1101 1100a 1101a

Comp.

Structure Comp.

Structure No. 1100b 1101b

1100c 1101c

1100d 1101d

1101e

1102 1103

1102a 1103a

Comp.

Structure Comp.

Structure No. 1102b 1103b

1104 1105

1104a 1105a

1104b 1105b

1106 1107

Comp.

Structure Comp.

Structure No. 1106a 1107a

1106b 1107b

1108 1109

1108a 1109a

1108b 1109b

Comp.

Structure Comp.

Structure No. 1110 1111

1110a 1110b

1112 1113

1113a 1113b

1114 1115a

Comp. Structure Comp. Structure No. 1115b 1116a 1116b 1117a 1117b 1118 1119 1004b 833 1007b

[001904] In one embodiment, a pharmaceutical composition is provided herein that comprises any species of NLRP3 antagonist defined herein (e.g., a compound or example from Tables 1A, 1E, 1F, B1, B2, B3, and B4; for example any one of examples 1 to 794) and a non-anti-TNFα agent disclosed herein. Preferably, where the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably, where the anti-TNFα agent is Adalimumab.

[001905] In one embodiment, a pharmaceutical combination of any species of NLRP3 antagonist defined herein is provided (e.g., a compound or example from Tables 1A, 1E, 1F, B1, B2, B3, and B4; for example any one of examples 1 to 794) and an anti-TNFα agent. Preferably, wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably, wherein the anti-TNFα agent is Adalimumab. Anti-TNFα Agents

[001906] The term "anti-TNFα agent" refers to an agent that directly or indirectly blocks, down-regulates, impairs, inhibits, impairs or reduces the activity and/or expression of TNFα . In some embodiments, an anti-TNFα agent is an antibody or antigen-binding fragment thereof, a fusion protein, a soluble TNFα receptor (a member of the soluble tumor necrosis factor 1A receptor superfamily (TNFR1), or a soluble tumor necrosis factor 1B receptor (TNFR2) superfamily), an inhibitory nucleic acid, or a small molecule TNFα antagonist. In some embodiments, the inhibitory nucleic acid is a ribozyme, a small hairpin-shaped RNA, a small interfering RNA, an antisense nucleic acid, or an aptamer.

[001907] Exemplary anti-TNFα agents that directly block, down-regulate, impair, inhibit or reduce the activity and/or expression of TNFα may, for example, inhibit or decrease the level of TNFα expression or a TNFα receptor (TNFR1 or TNFR2) on a cell (e.g., a cell obtained from a subject, a mammalian cell), or inhibit or reduce the binding of TNFα to its receptor (TNFR1 and/or TNFR2) and/or. Non-limiting examples of anti-TNFα agents that directly block, down-regulate, impair, inhibit or reduce the activity and/or expression of TNFα include an antibody or fragment thereof, a fusion protein, a soluble TNFα receptor ( for example, a soluble TNFR1 or soluble TNFR2), inhibitor nucleic acids (e.g., any of the examples of inhibitor nucleic acids described herein), and a small molecule TNFα antagonist.

[001908] Exemplary anti-TNFα agents that can indirectly block, down-regulate, impair, inhibit the activity and/or expression of TNFα can, for example, inhibit or decrease the level of signaling downstream of a TNFα receptor (eg, TNFR1 or TNFR2) in a mammalian cell (eg, decreasing the level and/or activity of one or more of the following signaling proteins: AP-1, mitogen-activated protein kinase 5 - nio (ASK1), inhibitor of nuclear factor kappa B (IKK), mitogen-activated protein kinase 8 (JNK), mitogen-activated protein kinase (MAPK), MEKK 1/4, MEKK 4/7, MEKK 3/6, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase 14 (NIK), receptor-interacting serine/threonine kinase 1 (RIP), death domain-associated TNFRSF1A (TRADD) and receptor-associated factor 2 TNF (TRAF2) in a cell) and/or decrease the level of TNFα-induced gene expression in a mammalian cell (e.g., decrease transcription of genes regulated by, for example, one or more transcription factors selected from the activation group of transcription factor 2 (ATF2), c-Jun and NF-κB). A description of downstream signaling from a TNFα receptor is provided in Wajant et al., Cell Death Differentiation 10:45 to 65, 2003 (incorporated herein by reference). For example, such indirect anti-TNFα agents can be an inhibitory nucleic acid that targets (decreases expression) a signaling component downstream of a TNFα-induced gene (e.g., any TNFα-induced gene known in the art). ), a TNFα receptor (e.g., any one or more of the downstream signaling components of a TNFα receptor described herein or known in the art), or a transcription factor selected from the group of NF-κB, c-Jun and ATF2.

[001909] In other examples, such indirect anti-TNFα agents may be a small molecule inhibitor of a protein encoded by a TNFα-induced gene (e.g., any protein encoded by a TNFα-induced gene known in the art), a small molecule inhibitor of a signaling component downstream of a TNFα receptor (e.g., any of the signaling components downstream of a TNFα receptor described herein or known in the art) and an inhibitor molecule of a transcription factor selected from the group of ATF2, c-Jun and NF-kB.

[001910] In other embodiments, anti-TNFα agents that can indirectly block, down-regulate, impair, or reduce one or more components of a cell (e.g., cells obtained from an individual, a mammalian cell) involved in signaling pathway that results in transcription of TNFα mRNA, stabilization of TNFα mRNA, and translation of TNFα mRNA (e.g., one or more components selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB , interleukin 1 receptor-associated kinase 1 (IRAK), JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, PKR, p38, AKT serine/threonine kinase 1 (rac), raf kinase (raf), ras, TRAF6, TTP). For example, such indirect anti-TNFα agents may be an inhibitory nucleic acid that targets (decreases expression) a component in a mammalian cell that is involved in the signaling pathway that results in transcription of TNFα mRNA, TNFα mRNA stabilization, and TNFα mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB,

IRAK, JNK, LBP, MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6 , TTP). In other examples, an indirect anti-TNFα agent is a small molecule inhibitor of a component in a mammalian cell that is involved in the signaling pathway that results in TNFα mRNA transcription, TNFα mRNA stabilization, and TNFα mRNA translation. TNFα (e.g. a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB, IRAK, JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP). antibodies

[001911] In some embodiments, the anti-TNFα agent is an antibody or an antigen-binding fragment thereof (eg, a Fab or an scFv). In some embodiments, an antibody or antigen-binding fragment of an antibody described herein may specifically bind TNFα. In some embodiments, an antibody or antigen-binding fragment described herein specifically binds to any one of TNFα, TNFR1, or TNFR2. In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can specifically bind to a TNFα receptor (TNFR1 or TNFR2).

[001912] In some embodiments, the antibody may be a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof. In some embodiments, an antibody can be an scFv-Fc, a VHH domain, a VNAR domain, a (scFv)2, a minibody, or a BiTE.

[001913] In some embodiments, an antibody can be a crossmab, a diabody, a scDiabody, a scDiabody-CH3, a Diacor-

po-CH3, a DutaMab, a DT-IgG, an Fc-diabody, a HAS-scDiabody, a cargo antibody pair, a Fab arm-switching antibody, a SEEDbody, a Triomab, a LUZ-Y, an Fcab , a kλ-body, an orthogonal Fab, a DVD-IgG, an IgG(H)-scFv, an scFv-(H)IgG, an IgG(L)-scFv, an scFv-(L)-IgG, an IgG (L,H)-Fc, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, a KIH IgG-scFab, a 2scFv-IgG , an IgG-2scFv, an scFv4-Ig, a Zibody, a DVI-IgG, a nanobody, an HSA-nanobody, a DVD-Ig, a double affinity targeting antibody (DART), a triomab, a kih IgG with common LC, an ortho-Fab IgG, a 2-in-1-IgG, IgG-ScFv, scFv2-Fc, a binanobody, tanden antibody, a DART-Fc, a scFv-HAS-scFv, a DAF (two-in-one or four-in-one), a DNL-Fab3, knobs-in-holes with common LC, knobs-in-holes assembly, a TandAb, a Triple Body, a mini-antibody, a mini-body, the TriBi mini- body, a scFv-CH3 KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab')2-scFV2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a scFv-Fc tandem, an intrabody, a bispecific dock and lock antibody, an ImmTAC, an HSAbody, a scFv in tandem, an IgG-IgG, a Cov-X-Body and a scFv1 -PEG-scFv2.

[001914] Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, an F(ab')2 fragment and a Fab' fragment. Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an antigen-binding fragment of an IgA (eg, an antigen-binding fragment of IgA1 or IgA2) ( for example an antigen-binding fragment of a human or humanized IgA, for example a human or humanized IgA1 or IgA2); an antigen-binding fragment of an IgD (eg, an antigen-binding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (eg, an antigen-binding fragment of a human or humanized IgE); an IgG (e.g. an antigen-binding fragment of IgG1, IgG2, IgG3 or IgG4) (e.g. an antigen-binding fragment of a human or humanized IgG, e.g. IgG1, IgG2, IgG3 or IgG4 human or humanized); or an antigen-binding fragment of an IgM (eg, an antigen-binding fragment of a human or humanized IgM).

[001915] Non-limiting examples of anti-TNFα agents that are antibodies that specifically bind to TNFα are described in Ben-Horin et al., Autoimmunity Rev. 13(1):24 to 30, 2014 ; Bongartz et al., JAMA 295(19):2275 to 2285, 2006; Butler et al., Eur. Cytokine Network 6(4):225 to 230, 1994; Cohen et al., Canadian J. Gastroenterol. Hepatol. 15(6):376 to 384, 2001; Elliott et al., Lancet 1994; 344:

1125 to 1127, 1994; Feldmann et al., Ann. Rev. Immunol. 19(1):163 to 196, 2001 ; Rankin et al., Br.J. Rheumatol. 2:334 to 342, 1995; Knight et al., Molecular Immunol. 30(16):1443 to 1453, 1993; Lorenz et al., J. Immunol. 156(4):1646 to 1653, 1996; Hinshaw et al., Circulatory Shock 30(3):279 to 292, 1990; Ordas et al., Clin. Pharmacol. Therapeutics 91(4):635 to 646, 2012; Feldman, Nature Reviews Immunol. 2(5):364 to 371, 2002; Taylor et al., Nature Reviews Rheumatol. 5(10):578 to 582, 2009; Garces et al., Annals Rheumatic Dis. 72(12):1947 to 1955, 2013; Palladino et al., Nature Rev. Drug Discovery 2(9):736 to 746, 2003; Sandborn et al., Inflammatory Bowel Diseases 5(2):119 to 133, 1999; Atzeni et al., Autoimmunity Reviews 12(7):703 to 708, 2013; Maini et al., Immunol. Rev. 144(1):195 to 223, 1995; Wanner et al., Shock 11(6):391 to 395, 1999; and US Patents

6,090,382; 6,258,562; and 6,509,015).

[001916] In certain embodiments, the anti-TNFα agent may include or is golimumab (golimumabTM), adalimumab (Humira™), infliximab (Remicade™), CDP571, CDP 870, or certolizumab pegol (Cimzia™).

In certain embodiments, the anti-TNFα agent may be a TNFα inhibitor biosimilar. Examples of approved late phase TNFα inhibitor biosimilars include, but are not limited to, infliximab biosimilars such as Flixabi™ (SB2) from Samsung Bioepis, Inflectra® (CT-P13) from Celltrion/Pfizer, GS071 from Aprogen, Remsima™, PF-06438179 from Pfizer/Sandoz, NI-071 from Nichi-Iko Pharmaceutical Co. and ABP 710 from Amgen; adalimumab biosimilars such as Amgevita® (ABP 501) from Amgen and Exemptia™ from Zydus Cadila, BMO-2 or MYL-1401-A from Biocon/Mylan, CHS-1420 from Coherus, FKB327 from Kyowa Kirin and BI 695501 from Boehringer Ingelheim;Solymbic®, SB5 from Samsung Bioepis, GP-2017 from Sandoz, ONS-3010 from Oncobiologics, M923 from Momenta, PF-06410293 from Pfizer, and etanercept biosimilars such as Erelzi™ from Sandoz/ Novartis, Brenzys™ (SB4) from Samsung Bioepis, GP2015 from Sandoz, TuNEX® from Mycenax, LBEC0101 from LG Life and CHS-0214 from Coherus.

[001917] In some embodiments of any of the methods described herein, the anti-TNFα agent is selected from the group consisting of: adalimumab, certolizumab, etanercept, golimumab, infliximab, CDP571 and CDP 870.

[001918] In some embodiments, any of the antibodies or antigen-binding fragments described herein have a dissociation constant (KD) of less than 1 x 10 -5 M (e.g., less than 0.5 x 10 -5 M, less than 1x10-6M, less than 0.5x10-6M, less than 1x10-7M, less than 0.5x10-7M, less than 1x10-8M , less than 0.5x10-8M, less than 1x10-9M, less than 0.5x10-9M, less than 1x10-10M, less than 0.5x10-10 M, less than 1 x 10-11 M, less than 0.5 x 10-11 M, or less than 1 x 10-12 M), for example, as measured in phosphate-buffered saline using surface (SPR).

[001919] In some embodiments, any of the antibodies or antigen-binding fragments described herein have a K D of about 1 x 10 -12 M to about 1 x 10 -5 M, about 0.5 x 10 -5M, about 1x10-6M, about 0.5x10-6M, about 1x10-7M, about 0.5x10-7M, about 1x10- 8M, about 0.5x10-8M, about 1x10-9M, about 0.5x10-9M, about 1x10-10M, about 0.5x10 -10 M, about 1 x 10 -11 M, or about 0.5 x 10 -11 M (inclusive); about 0.5 x 10-11 M to about 1 x 10-5 M, about 0.5 x 10-5 M, about 1 x 10-6 M, about 0.5 x 10- 6M, about 1x10-7M, about 0.5x10-7M, about 1x10-8M, about 0.5x10-8M, about 1x10-9 M, about 0.5 x 10 -9 M, about 1 x 10 -10 M, about 0.5 x 10 -10 M, or about 1 x 10 -11 M (inclusive); about 1x10-11M to about 1x10-5M, about 0.5x10-5M, about 1x10-6M, about 0.5x10-6M, about 1x10-7M, about 0.5x10-7M, about 1x10-8M, about 0.5x10-8M, about 1x10-9M, about 0.5 x 10 -9 M, about 1 x 10 -10 M, or about 0.5 x 10 -10 M (inclusive); about 0.5x10-10M to about 1x10-5M, about 0.5x10-5M, about 1x10-6M, about 0.5x10-6M , about 1x10-7M, about 0.5x10-7M, about 1x10-8M, about 0.5x10-8M, about 1x10-9M, about 0.5 x 10 -9 M, or about 1 x 10 -10 M (inclusive); about 1x10-10M to about 1x10-5M, about 0.5x10-5M, about 1x10-6M, about 0.5x10-6M, about 1x10-7M, about 0.5x10-7M, about 1x10-8M, about 0.5x10-8M, about 1x10-9M, or about 0.5 x 10 -9 M (inclusive); about 0.5x10-9M to about 1x10-5M, about 0.5x10-5M, about 1x10-6M, about 0.5x10-6M , about 1 x 10-7 M, about 0.5 x 10-7 M, about 1 x 10-8 M, about 0.5 x 10-8 M, or about 1 x 10-8 9 M (inclusive); about 1x10-9M to about 1x10-5M, about 0.5x10-5M, about 1x10-6M, about 0.5x10-6M , about 1 x 10 -7 M, about 0.5 x 10 -7 M, about 1 x 10 -8 M, or about 0.5 x 10 -8 M (inclusive); about 0.5 x 10-8M to about 1 x 10-5M, about

0.5x10-5M, about 1x10-6M, about 0.5x10-6M, about 1x10-7M, about 0.5x10-7M, or about 1 x 10-8 M (inclusive); about 1x10-8M to about 1x10-5M, about 0.5x10-5M, about 1x10-6M, about 0.5x10-6M, about from 1 x 10 -7 M, or about 0.5 x 10 -7 M (inclusive); about 0.5x10-7M to about 1x10-5M, about 0.5x10-5M, about 1x10-6M, about 0.5x10-6M , or about 1 x 10 -7 M (inclusive); about 1x10-7M to about 1x10-5M, about 0.5x10-5M, about 1x10-6M, or about 0.5x10-6M ( including); about 0.5 x 10 -6 M to about 1 x 10 -5 M, about 0.5 x 10 -5 M, or about 1 x 10 -6 M (inclusive); about 1 x 10 -6 M to about 1 x 10 -5 M or about 0.5 x 10 -5 M (inclusive); or about 0.5 x 10 -5 M to about 1 x 10 -5 M (inclusive), for example, as measured in phosphate-buffered saline using surface plasmon resonance (SPR).

[001920] In some embodiments, any of the antibodies or antigen-binding fragments described herein have a Koff of about 1 x 10 -6 s -1 to about 1 x 10 -3 s -1 , about 0 .5 x 10-3 s-1, about 1 x 10-4 s-1, about 0.5 x 10-4 s-1, about 1 x 10-5 s-1, or about 0, 5 x 10-5 s-1 (inclusive); about 0.5 x 10-5 s-1 to about 1 x 10-3 s-1, about 0.5 x 10-3 s-1, about 1 x 10-4 s-1, about 0.5 x 10 -4 s -1 , or about 1 x 10 -5 s -1 (inclusive); about 1 x 10-5 s-1 to about 1 x 10-3 s-1, about 0.5 x 10-3 s-1, about 1 x 10-4 s-1, or about 0 .5 x 10 -4 s -1 (inclusive); about 0.5 x 10-4 s-1 to about 1 x 10-3 s-1, about 0.5 x 10-3 s-1, or about 1 x 10-4 s-1 (inclusive ); about 1 x 10 -4 s -1 to about 1 x 10 -3 s -1 , or about 0.5 x 10 -3 s -1 (inclusive); or about 0.5 x 10-5 s-1 to about 1 x 10-3 s-1 (inclusive), for example, as measured in phosphate-buffered saline using surface plasmon resonance (SPR) .

[001921] In some embodiments, any of the antibodies or antigen-binding fragments described herein have a Kon of about 1 x 10 2 M-1s-1 to about 1 x 10 6 M-1s-1, about 0 .5 x 106 M-1s-1, about 1 x 105 M-1s-1, about 0.5 x 105 M-1s-1, about 1 x 104 M-1s-1, about 0.5 x 10 4 M-1s-1, about 1 x 10 3 M-1s-1, or about 0.5 x 10 3 M-1s-1 (inclusive); about 0.5 x 103 M-1s-1 to about 1 x 106 M-1s-1, about 0.5 x 106 M-1s-1, about 1 x 105 M-1s-1, about 0.5 x 10 5 M-1s-1, about 1 x 10 4 M-1s-1, about 0.5 x 10 4 M-1s-1, or about 1 x 10 3 M-1s-1 (inclusive); about 1 x 103 M-1s-1 to about 1 x 106 M-1s-1, about 0.5 x 106 M-1s-1, about 1 x 105 M-1s-1, about 0, 5 x 10 5 M-1s-1, about 1 x 10 4 M-1s-1, or about 0.5 x 10 4 M-1s-1 (inclusive); about 0.5 x 104 M-1s-1 to about 1 x 106 M-1s-1, about 0.5 x 106 M-1s-1, about 1 x 105 M-1s-1, about 0.5 x 10 5 M-1-1s, or about 1 x 10 4 M-1s-1 (inclusive); about 1 x 104 M-1s-1 to about 1 x 106 M-1s-1, about 0.5 x 106 M-1s-1, about 1 x 105 M-1s-1, or about 0.5 x 105 M-1s-1 (inclusive); about 0.5 x 105 M-1s-1 to about 1 x 106 M-1s-1, about 0.5 x 106 M-1s-1, or about 1 x 105 M-1s-1 (inclusive ); about 1 x 10 5 M-1s-1 to about 1 x 10 6 M-1s-1, or about 0.5 x 10 6 M-1s-1 (inclusive); or about 0.5 x 106 M-1s-1 to about 1 x 106 M-1s-1 (inclusive), for example, as measured in phosphate-buffered saline using surface plasmon resonance ( SPR). Fusion Proteins

[001922] In some embodiments, the anti-TNFα agent is a fusion protein (e.g., an extracellular domain of a TNFR fused to a partner peptide, e.g., an Fc region of an immunoglobulin, e.g. human IgG) (see, for example, Deeg et al., Leukemia 16(2):162, 2002; Peppel et al., J. Exp. Med. 174(6):1483 to 1489, 1991) or a Soluble TNFR (eg, TNFR1 or TNFR2) that specifically binds TNFα. In some embodiments, the anti-TNFα agent includes or is a soluble TNFα receptor (e.g., Bjornberg et al., Lymphokine Cytokine Res.

13(3):203 to 211, 1994; Kozak et al., Am.J. Physiol. Reg. Integrative Comparative Physiol. 269(1):R23-R29, 1995; Tsao et al., Eur Respir J. 14(3):490 to 495, 1999 ; Watt et al., J Leukoc Biol. 66(6):1005 to 1013, 1999; Mohler et al., J. Immunol. 151(3):1548 to 1561, 1993; Nophar et al., EMBO J. 9(10):3269, 1990; Piguet et al., Eur. Respiratory J. 7(3):515 to 518, 1994; and Gray et al., Proc. natl. academy Sci. U.S.A. 87(19):7380 to 7384, 1990). In some embodiments, the anti-TNFα agent includes or is etanercept (Enbrel™) (see, for example, WO 91/03553 and WO 09/406476, incorporated by reference herein). In some embodiments, the anti-TNFα agent inhibitor includes or is r-TBP-I (e.g., Gradstein et al., J. Acquir. Immune Defic. Synndr. 26(2): 111 to 117, 2001) . Inhibitory Nucleic Acids

[001923] Inhibitory nucleic acids that can decrease the expression of AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4 , MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA expression in a mammalian cell include antisense nucleic acid molecules, that is, nucleic acid molecules whose nucleotide sequence is completely or partially complementary to all or part of an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras , raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP mRNA (e.g., fully or partially complementary to all or part of any of the sequences shown in Table E). Table E. Human gene GenBank mRNA accession number (or numbers)

Human gene GenBank accession number (or numbers) of mRNA Tumor necrosis factor (TNF, NM_000594 also known as TNF-alpha) Member of the TNF receptor superfamily NM_001065 (TNFRSF1A) (also NM_001346091 also known as TNFR1 ) NM_001346092 member of the superfamily of TNF recep- tor NM_001066 1B (TNFRSF1B) (XM_011542060 tam- well known as TNFR2) XM_011542063 XM_017002214 XM_017002215 XM_017002211 associated death domain NM_003789 TNFRSF1A (TRADD) NM_001323552 XM_005256213 XM_017023815 factor associated with TNF receptor 2 NM_021138 (TRAF2) XM_011518976 XM_011518977 XM_011518974 protooncogene JunD, NM_001286968 subunit of AP-1 NM_005354 transcription factor (JUND) kinase kinase kinase protein NM_005923 mitogen-activated 5 (MAP3K5) XM_017010875 (also known as ASK1) XM_017010872 XM_017010873 XM_017010877 XM_017010874 XM_017010871 XM_017010870 XM_017010876 XM_011535839

Human gene (or numbers) access to MRNA Genbank access CD14 nm_000591 nm_001040021 nm_001174104 nm_001174104 nm_001174105 kinase protein activated by mite-nm_001040056 Genius 3 (MAPK3) (also known as ERK1) nm_002746 protein kinase activated by myth-nm_002745 genius 1 ( MAPK1) (NM_138957 also knowl- acid as ERK2) inhibitor NM_001190720 kinase beta subunit of nuclear factor kappa B NM_001242778 (IKBKB) NM_001556 XM_005273491 XM_005273496 XM_005273493 XM_005273498 XM_011544518 XM_005273492 XM_005273490 XM_005273494 XM_011544521 XM_011544522 XM_005273495 XM_011544517 12XM_017013396 XM_011544520 XM_011544519 NFKB inhibitor alpha (NFKBIA) NM_020529 NM_001025242 Interleukin 1 Receptor Associated Kinase 1 (IRAK1) NM_001025243 NM_001569 XM_005274668

Human Gene number (or numbers) for access to the mRNA GenBank Protein kinase activated by mito- NM_001278547 Genius 8 (MAPK8) (also knowl- NM_001278548 acid as JNK) NM_001323302 NM_001323320 NM_001323321 NM_001323322 NM_001323323 NM_001323324 NM_001323325 NM_001323326 NM_001323327 NM_001323328 NM_001323329 NM_001323330 NM_001323331 NM_139046 NM_139049 XM_024448079 XM_024448080 lipopolissa- the binding protein NM_004139 Carideo (LBP) activated protein kinase kinase 1 NM_002755 mitogen (MAP2K1) (XM_017022411 tam- well known as MEK1) XM_011521783 XM_017022412 XM_017022413 kinase kinase mitogen activated protein 2 NM_030662 (MAP2K2) (XM_006722799 tam- also known as MEK2) XM_017026990 XM_017026989 XM_017026991

Human Gene number (or numbers) GenBank Accession mRNA NM_001316332 activated protein kinase kinase mitogen-3 (MAP2K3) (NM_002756 tam- well known as MEK3) NM_145109 XM_017024859 XM_005256723 XM_017024857 XM_011523959 XM_017024858 XM_011523958 activated protein kinase kinase mitogen NM_001330450 6 (MAP2K6 ) (NM_002758 tam- well known as MEK6) XM_005257516 XM_011525027 XM_011525026 XM_006721975 NM_005921 Protein kinase kinase kinase mitogen-activated 1 (MAP3K1) XM_017009485 (also known as MEKK1) XM_017009484 NM_001330431 kinase kinase Protein kinase mitogen-activated 3 (MAP3K3) NM_001363768 (also known as MEKK3) NM_002401 NM_203351 XM_005257378 kinase kinase kinase mitogen-activated protein NM_001291958 4 (MAP3K4) NM_001301072 (also known as MEKK4) XM_017010869 NM_001363582 NM_005922 NM_006724 NM_001297609 kinase kinase Protein kinase mitogen-activated 6 (MAP3K6) NM_004672 (also known as MEKK6) X M_017002771 XM_017002772

Human gene number (or numbers) of access to mRNA protein kinase kinase kinase kinase nm_003188 activated by mitogen 7 (MAP3K7) nm_145331 (also known as mekk7) nm_145332 nm_145333 xm_006715553 XM_017011226 protein kinase activated by nm_004759 MAPK 2 (MAPKAPK2) (also NM_032960 as MK2) XM_005273353 XM_017002810 MyD88, NM_001172566 transducing adapter innate immune signal NM_001172567 (MyD88) NM_001172568 NM_001172569 NM_001365876 NM_001365877 NM_002468 1 subunit of nuclear factor NM_001165412 kappa B (NFKB1) NM_001319226 NM_003998 XM_024454069 XM_024454067 XM_011532006 XM_024454068 kinase kinase kinase protein NM_003954 mitogen-activated 14 XM_011525441 (MAP3K14) (aka NIK)

human gene number (or numbers) access to kinase mRNA GenBank protein activated by mito- NM_001315 genius 14 (MAPK14) (also co-NM_139012 nhecido as p38) NM_139013 NM_139014 XM_011514310 XM_017010300 XM_017010299 XM_017010301 XM_017010304 XM_017010303 XM_017010302 XM_006714998 Kinase 2 alpha factor NM_001135651 initiating eukaryotic translation 2 NM_001135652 (EIF2AK2) (also known NM_002759 as PKR) XM_011532987 XM_017004503 AKT serine / threonine kinase 1 NM_001014431 (AKT1) (also known as NM_001014432 RAC) NM_005163 zinc fingers and homeoboxes 2 NM_001362797 (ZHX2) (also known as NM_014943 RAF) XM_011516932 XM_005250836 proto-oncogene KRAS, GTPase NM_001369786 (KRAS) NM_001369787 NM_004985 NM_033360 proto-oncogene NRAS, GTPase NM_002524 (NRAS)

Human Gene number (or numbers) to access Serine GenBank mRNA NM_001317061 interaction with recep- tor / threonine kinase 1 (RIPK1) NM_001354930 (also known as RIP) NM_001354931 NM_001354932 NM_001354933 NM_001354934 NM_003804 XM_017011405 XM_006715237 XM_017011403 XM_017011404 factor associated with TNF receptor NM_004620 6 (TRAF6) NM_145803 XM_017018220 Ring finger protein ZFP36 NM_003407 (ZFP36) (also known as TTP)

[001924] An antisense nucleic acid molecule may be completely or partially complementary to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding an AP-1, ASK1, CD14, c -jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP protein. Non-coding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.

[001925] Based on the sequences disclosed herein, one skilled in the art can easily choose and synthesize any one of several suitable antisense nucleic acids to target a nucleic acid encoding an AP-1, ASK1, CD14, c -jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2,

MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or described TTP protein in this document. Antisense nucleic acids that target a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP protein can be designed with the use of the software available on the Integrated DNA Technologies website.

[001926] An antisense nucleic acid can have, for example, about 5, 10, 15, 18, 20, 22, 24, 25, 26, 28, 30, 32, 35, 36, 38, 40, 42, 44 , 45, 46, 48, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using enzymatic linkage reactions and chemical synthesis using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using nucleotides modified in various ways or naturally occurring nucleotides designed to increase the physical stability of the duplex formed between antisense and sense nucleic acids, for example, derived from phosphorothioate and acridine-substituted nucleotides or to increase the biological stability of the molecules.

[001927] Examples of modified nucleotides that can be used to generate an antisense nucleic acid include 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 2-methylthio-N6 -isopentenyladenine, uracil-5-oxyacetic acid (v), wibutoxosine, pseudouracil, cheosine, 2-thiocytosine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, uracil 5- (carboxyhydroxylmethyl), 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-

isopentenyladenine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 5-methyl-2-thiouracil, 2 -thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxy-acetic acid methyl ester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N- 2-carboxypropyl)uracil, (acp3)w and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector in which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will have an antisense orientation to an antisense nucleic acid). nucleotide of interest).

[001928] The antisense nucleic acid molecules described herein may be prepared in vitro and administered to a subject, for example, a human subject. Alternatively, they can be generated in situ so that they hybridize to or bind to cellular mRNA and/or genomic DNA encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD , TRAF2, TRAF6 or TTP protein to thereby inhibit expression, for example by inhibiting transcription and/or translation. Hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the groove. main part of the double helix. Antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., an adenovirus vector, a lentivirus, or a retrovirus).

[001929] An antisense nucleic acid may be an α-anomeric nucleic acid molecule. An α-nucleic acid molecule

anomeric form specific double-stranded hybrids with complementary RNA, in which, unlike the usual β units, the strands are parallel to each other (Gaultier et al., Nucleic Acids Res. 15:6625 to 6641, 1987). The antisense nucleic acid may also comprise a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327 to 330, 1987) or a 2'-O-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15 :6,131 to 6,148, 1987).

[001930] Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP mRNA, eg specificity for one of the sequences shown in Table E). Ribozymes are catalytic RNA molecules with ribonuclease activity that can cleave a single-stranded nucleic acid, such as an mRNA, for which they have a complementary region. Thus, ribozymes (e.g. hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585 to 591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation. of the protein encoded by the mRNA. An AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP mRNA can be used to select a catalytic RNA that has a specific ribonuclease activity of a grouping of RNA molecules. See, for example, Bartel et al., Science 261:1411 to 1418, 1993.

[001931] Alternatively, a ribozyme that has specificity for an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB,

NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP mRNA can be designed based on the nucleotide sequence of any of the AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38 , PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP mRNA sequences disclosed herein (e.g., Table E). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved into an AP-1, ASK1, CD14, c-jun, ERK1 /2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP mRNA (see, for example, US Patent Nos. 4,987,071 and 5,116,742).

[001932] An inhibitor nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of a polypeptide AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3 /6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the polypeptide AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6 or TTP (e.g. promoter and/or enhancer , for example, a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the initial state of transcriptional initiation) to form triple helical structures that prevent transcription of the gene in target cells. See, generally, Maher, Bioassays 14(12):807 to 815, 1992; Helene, Anticancer Drug Des. 6(6):569 to 84, 1991; and Helene, Ann. N.Y. Acad. Sci. 660:27 to 36, 1992.

[001933] In various embodiments, the inhibitory nucleic acids can be modified in the sugar chemical moiety, the base chemical moiety or the phosphate backbone to improve, for example, the solubility, stability or hybridization of the molecule. For example, the deoxyribose phosphate backbone of nucleic acids can be modified to generate peptide nucleic acids (see, for example, Hyrup et al., Bioorganic Medicinal Chem. 4(1):5 to 23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, eg DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows specific hybridization with RNA and DNA under conditions of low ionic strength. PNA oligomers can be synthesized using standard solid-phase peptide synthesis protocols (see, for example, Perry-O'Keefe et al., Proc. Natl. Acad. Sci. USA 93:14670 to 14675, 1996). PNAs can be used as antisense or antigen agents for sequence-specific modulation of gene expression, for example, inducing transcription or translation interruption or inhibiting replication. small molecules

[001934] In some embodiments, the anti-TNFα agent is a small molecule. In some embodiments, the small molecule is a tumor necrosis factor converting enzyme (TACE) inhibitor (eg, Moss et al., Nature Clinical Practice Rheumatology 4: 300 to 309, 2008). In some embodiments, the anti-TNFα agent is C87 ( Ma et al., J. Biol. Chem. 289(18):12457 to 12466, 2014 ). And bad-

In some embodiments, the small molecule is LMP-420 (eg, Haraguchi et al., AIDS Res. Ther. 3:8, 2006). In some embodiments, the TACE inhibitor is TMI-005 and BMS-561392. Additional examples of small molecule inhibitors are described, for example, in He et al., Science 310(5750):1022 to 1025, 2005.

[001935] In some examples, the anti-TNFα agent is a small molecule that inhibits the activity of one of AP-1, ASK1, IKK, JNK, MAPK, MEKK 1/4, MEKK4/7, MEKK 3/6, NIK , TRADD, RIP, NF-κB, and TRADD in a cell (eg, in a cell obtained from an individual, a mammalian cell).

[001936] In some examples, the anti-TNFα agent is a small molecule that inhibits the activity of one of CD14, MyD88 (see e.g. Olson et al., Scientific Reports 5:14246, 2015), ras (e.g. , Baker et al., Nature 497:577-578, 2013), raf (e.g. vemurafenib (PLX4032, RG7204), sorafenib tosylate, PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265 (CHIR-265 ), AZ 628, NVP-BHG712, SB590885, ZM 336372, sorafenib, GW5074, TAK-632, CEP-32496, encorafenib (LGX818), CCT196969, LY3009120, RO5126766 (CH5126766), PLX79044 and MLN).

[001937] In some examples, the TNFα inhibitor of the anti-TNFα agent is a small molecule that inhibits the activity of one of MK2 (PF 3644022 and PHA 767491), JNK (e.g. AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), c-jun (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S , JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), MEK3/6 (e.g., Akinleye et al., J. Hematol. Oncol. 6:27, 2013), p38 (eg example, AL 8697, AMG 548, BIRB 796, CMPD-1, DBM dihydrochloride 1285, EO 1428, JX 401, ML 3403, Org 48762-0, PH 797804, RWJ 67657, SB 202190, SB 203580, SB 239063 706504, SCIO 469, SKF 86002, SX 011, TA 01, TA 02,

TAK 715, VX 702, and VX 745), PKR (eg, 2-aminopurine or CAS 608512-97-6), TTP (eg, CAS 329907-28-0), MEK1/2 (eg, Facciorusso et al. al., Expert Review Gastroentrol. Hepatol. 9:993-1003, 2015), ERK1/2 (e.g., Mandal et al., Oncogene 35:2547 to 2561, 2016), NIK (e.g. Mortier et al., Bioorg. Med. Chem. Lett. 20:4515 to 4520, 2010 ), IKK (e.g. Reilly et al., Nature Med. 19:313-321, 2013), IκB (e.g. Suzuki et al., Ex - pert. Opin. Invest. Drugs 20:395 to 405, 2011 ), NF-κB (e.g. Gupta et al., Biochim. Biophys. Acta 1799(10-12):775 to 787, 2010), rac ( for example, US Patent No. 9,278,956 ), MEK4/7, IRAK ( Chaudhary et al., J. Med. Chem. 58(1):96 to 110, 2015 ), LBP (see, for example, the patent No. US 5,705,398) and TRAF6 (e.g. 3-[(2,5-Dimethylphenyl)amino]-1-phenyl-2-propen-1-one).

[001938] In some embodiments of any of the methods described herein, the inhibitory nucleic acid can be from about 10 nucleotides to about 50 nucleotides (e.g., about 10 nucleotides to about 45 nucleotides, about 10 nucleotides). nucleotides to about 40 nucleotides, about 10 nucleotides to about 35 nucleotides, about 10 nucleotides to about 30 nucleotides, about 10 nucleotides to about 28 nucleotides, about 10 nucleotides to about 26 nucleotides , about 10 nucleotides to about 25 nucleotides, about 10 nucleotides to about 24 nucleotides, about 10 nucleotides to about 22 nucleotides, about 10 nucleotides to about 20 nucleotides, about 10 nucleotides to about 20 nucleotides 18 nucleotides, about 10 nucleotides to about 16 nucleotides, about 10 nucleotides to about 14 nucleotides, about 10 nucleotides to about 12 nucleotides, about 12 nucleotides to about 50 nucleotides , about 12 nucleotides to about 45 nucleotides, about 12 nucleotides to about 40 nucleotides, about 12 nucleotides to about 35 nucleotides,

about 12 nucleotides to about 30 nucleotides, about 12 nucleotides to about 28 nucleotides, about 12 nucleotides to about 26 nucleotides, about 12 nucleotides to about 25 nucleotides, about 12 nucleotides about 24 nucleotides, about 12 nucleotides to about 22 nucleotides, about 12 nucleotides to about 20 nucleotides, about 12 nucleotides to about 18 nucleotides, about 12 nucleotides to about 16 nucleotides, about 12 nucleotides about 14 nucleotides, about 15 nucleotides to about 50 nucleotides, about 15 nucleotides to about 45 nucleotides, about 15 nucleotides to about 40 nucleotides, about 15 nucleotides to about 35 nucleotides, about 15 nucleotides to about 30 nucleotides, about 15 nucleotides to about 28 nucleotides, about 15 nucleotides to about 26 nucleotides, about 15 nucleotides to about 25 nucleotides, about 15 nucleotides to about d and 24 nucleotides, about 15 nucleotides to about 22 nucleotides, about 15 nucleotides to about 20 nucleotides, about 15 nucleotides to about 18 nucleotides, about 15 nucleotides to about 16 nucleotides, about 16 nucleotides to about 50 nucleotides, about 16 nucleotides to about 45 nucleotides, about 16 nucleotides to about 40 nucleotides, about 16 nucleotides to about 35 nucleotides, about 16 nucleotides to about 30 nucleotides, about 16 nucleotides to about 28 nucleotides, about 16 nucleotides to about 26 nucleotides, about 16 nucleotides to about 25 nucleotides, about 16 nucleotides to about 24 nucleotides, about 16 nucleotides to about 22 nucleotides, about 16 nucleotides to about 20 nucleotides, about 16 nucleotides to about 18 nucleotides, about 18 nucleotides to about 20 nucleotides, about 20 nucleotides to about 50 nucleotides, about 20 nu - cleotides to about 45 nucleotides, about 20 nucleotides to about

about 40 nucleotides, about 20 nucleotides to about 35 nucleotides, about 20 nucleotides to about 30 nucleotides, about 20 nucleotides to about 28 nucleotides, about 20 nucleotides to about 26 nucleotides, about 20 nucleotides to about 25 nucleotides, about 20 nucleotides to about 24 nucleotides, about 20 nucleotides to about 22 nucleotides, about 24 nucleotides to about 50 nucleotides, about 24 nucleotides to about 45 nucleotides , about 24 nucleotides to about 40 nucleotides, about 24 nucleotides to about 35 nucleotides, about 24 nucleotides to about 30 nucleotides, about 24 nucleotides to about 28 nucleotides, about 24 nucleotides to about 28 nucleotides 26 nucleotides, about 24 nucleotides to about 25 nucleotides, about 26 nucleotides to about 50 nucleotides, about 26 nucleotides to about 45 nucleotides, about 26 nucleotides to about 40 nucleotides, about 26 nucleotides nucleotides to about 35 nucleotides, about 26 nucleotides to about 30 nucleotides, about 26 nucleotides to about 28 nucleotides, about 28 nucleotides to about 50 nucleotides, about 28 nucleotides to about 45 nucleotides, about from 28 nucleotides to about 40 nucleotides, about 28 nucleotides to about 35 nucleotides, about 28 nucleotides to about 30 nucleotides, about 30 nucleotides to about 50 nucleotides, about 30 nucleotides to about 45 nu - cleotides, about 30 nucleotides to about 40 nucleotides, about 30 nucleotides to about 38 nucleotides, about 30 nucleotides to about 36 nucleotides, about 30 nucleotides to about 34 nucleotides, about 30 nucleotides to about 32 nucleotides, about 32 nucleotides to about 50 nucleotides, about 32 nucleotides to about 45 nucleotides, about 32 nucleotides to about 40 nucleotides, about 32 nucleotides to about 35 nucleotides tides, about 35 nucleotides to about 50 nucleotides,

about 35 nucleotides to about 45 nucleotides, about 35 nucleotides to about 40 nucleotides, about 40 nucleotides to about 50 nucleotides, about 40 nucleotides to about 45 nucleotides, about 42 nucleotides to about 50 nucleotides, about 42 nucleotides to about 45 nucleotides, or about 45 nucleotides to about 50 nucleotides) in length. One skilled in the art will understand that inhibitor nucleic acids may comprise at least one nucleic acid modified at the 5' or 3' end of the DNA or RNA.

[001939] In some embodiments, the inhibitor nucleic acid may be formulated into a liposome, a micelle (e.g., a mixed micelle), a nanoemulsion or a microemulsion, a solid nanoparticle or a nanoparticle (e.g., a nanoparticle including - of one or more synthetic polymers). Additional exemplary structural features of inhibitory nucleic acids and inhibitor nucleic acid formulations are described in US 2016/0090598 .

[001940] In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) may include sterile saline (e.g., phosphate-buffered saline (PBS)). In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) may include a tissue-specific delivery molecule (e.g., a tissue-specific antibody). Pharmaceutical Compositions and General Administration

[001941] In some embodiments, a chemical entity (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients and, optionally, one or more additional therapeutic agents, as described herein.

[001942] In some embodiments, the chemical entities may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as 1000 polyethylene glycol d-α-tocopherol succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, whey proteins such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial mixtures of glycerides of acids saturated vegetable fats, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyoxypropylene-polyethylene block polymers and wool fat. Cyclodextrins, such as α-, β- and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to improve delivery of described compounds. in this document. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance consisting of non-toxic excipient may be prepared. The contemplated compositions may contain

0.001% to 100% of a chemical entity provided in this document, in one modality, 0.1 to 95%, in another modality, 75 to 85%, in another modality, 20 to 80%. Actual methods for preparing such dosage forms are known, or will be appreciated, to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[001943] In some embodiments, an NLRP3 antagonist and/or an anti-TNFα agent disclosed herein is administered as a pharmaceutical composition that includes the NLRP3 antagonist and/or anti-TNFα agent and one or more excipients pharmaceutically acceptable agents and, optionally, one or more additional therapeutic agents, as described herein. Preferably, the pharmaceutical composition which includes an NLRP3 antagonist and an anti-TNFα agent.

[001944] Preferably, the above pharmaceutical composition modalities comprise an NLRP3 antagonist disclosed herein. More preferably, the above pharmaceutical composition modalities comprise an NLRP3 antagonist and an anti-TNFα agent disclosed herein. Administration Routes and Composition Components

[001945] In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof may be administered to the individual in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinus, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal. , intraduodenal, intradural, intra-epidermal, intra-esophageal, intragastric, intragingival, intra-

traileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasignal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtraceal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (eg, intratumoral).

[001946] The compositions can be formulated for parenteral administration, for example, formulated for injection by the intravenous, intramuscular, subcutaneous or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, as liquid solutions or suspensions; solid forms suitable for use in preparing solutions or suspensions may also be prepared after the addition of a liquid prior to injection; and the preparations can also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of the present disclosure.

[001947] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the point where it can be easily injected. It must also be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi.

[001948] The carrier can also be a dispersion medium or solvent containing, for example, water, ethanol, polyol (for example, glycol

cerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures thereof and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents which delay absorption, for example, aluminum monostearate and gelatin.

[001949] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and the other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile filtered solution of the same. .

[001950] Intratumoral injections are discussed, for example, in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems" Neoplasm. 2006, 10, 788 to 795.

[001951] In certain embodiments, the chemical entities described herein or a pharmaceutical composition thereof are suitable for local topical administration of the digestive tract or GI, for example, rectal administration. Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gelatin suppositories, and enemas (e.g., retention enemas).

[001952] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema or rectal suppository include, without limitation, any one or more glycerides from cocoa butter, synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol , sweet almond oil, sorbitol, sodium benzoate, anoxic SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cogoil caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonyl methane (MSM), lactic acid, glycine, vitamins such as vitamin A and E and potassium acetate.

[001953] In certain embodiments, suppositories may be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or a suppository wax that are solid at room temperature. , but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[001954] In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or gastrointestinal tract orally (e.g., solid or liquid dosage forms).

[001955] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical entity is admixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar, carbonate calcium, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and its mixtures. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft or hard filled gelatine capsules with the use of such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[001956] In one embodiment, the compositions will take the form of a unit dosage form, such as a pill or tablet, and therefore, the composition may contain, along with a chemical entity provided herein, a diluent, such as lactose, sucrose , phospha-

dicalcium or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule) . Also contemplated are unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated; for example, capsules with granules (or tablets in a capsule) of each drug; two-layer tablets, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[001957] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives which are particularly useful in preventing the growth or action of microorganisms. Several preservatives are well known and include, for example, phenol and ascorbic acid.

[001958] In certain embodiments, the excipients are sterile and generally free of undesirable matter. Such compositions may be sterilized by conventional, known sterilization techniques. For many oral dosage form excipients, such as tablets and capsules, sterility is not required. The USP/NF standard is usually sufficient.

[001959] In certain embodiments, the solid oral dosage forms may further include one or more components that chemically and/or structurally predispose the composition to deliver the chemical entity to the stomach or lower GI; for example, the ascending colon and/or transverse colon and/or distal colon and/or small intestine. Exemplary formulation techniques are described in, for example,

eg Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776 to 802, which is incorporated herein by reference in its entirety.

[001960] Examples include upper GI targeting techniques, eg Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[001961] Other examples include targeting techniques for the low GI. To target various regions of the intestinal tract, various enteric/pH-sensitive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or corrode at specific pH ranges selected based on the GI region of desired drug release. These materials also function to protect acid-labile drugs from the gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (acetate phthalate) series). polyvinyl), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers) and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, pressure-controlled colonic administration capsule, and Pulsincap.

[001962] Ocular compositions may include, without limitation, one or more of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene Glycol); Stabilizers (eg Pluronic (triblock copolymers), Cyclodextrins); Preservatives (eg, Benzalkonium Chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorine complex; Allergan, Inc.).

[001963] Topical compositions may include ointments and creams. Ointments are semi-solid preparations that are typically based on

in petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous or semi-solid liquid emulsions, usually oil-in-water or water-in-oil. Cream bases are typically water washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the "internal" phase, is generally composed of petroleum and a fatty alcohol, such as cetyl or stearyl alcohol; the water phase usually, though not necessarily, exceeds the oil phase in volume and usually contains a humectant. The emulsifier in a cream formulation is usually a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base must be inert, stable, non-irritating and non-sensitizing.

[001964] In any of the foregoing embodiments, the pharmaceutical compositions described herein may include one or more of the following: lipids, multilamellar vesicles cross-linked between layers, nanoparticles or microparticles based on poly(Acid D, L -lactic-co-glycolic) based on [PLGA] or nanoparticles or microparticles and lipid bilayers supported by nanoporous particles. Enema formulations

[001965] In some embodiments, enema formulations containing the chemical entities described herein are provided in "ready-to-use" form.

[001966] In some embodiments, enema formulations containing the chemical entities described herein are provided in one or more kits or packages. In certain embodiments, the kit or package includes two or more separately contained/packaged components, e.g. two components, which when mixed together provide the desired formulation (e.g., as a suspension).

they are). In some of these embodiments, the two-component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the chemical entity (as described herein in anywhere) and, optionally, one or more pharmaceutically acceptable excipients (e.g., formulated together as a solid preparation, e.g., formulated together as a wet granulate solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and, optionally, one or more other pharmaceutically acceptable excipients together, forming a liquid carrier. Prior to use (e.g. immediately prior to use), the contents of (i) and (ii) are combined to form the desired enema formulation, eg as a suspension. In other embodiments, each of components (i) and (ii) is supplied in its own kit or separate package.

[001967] In some embodiments, each of the one or more liquids is water, or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents. Such typical solvents include, without limitation, glycerol, ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. In certain modalities, each of the one or more liquids is water. In other embodiments, each of the one or more liquids is an oil, for example natural and/or synthetic oils that are commonly used in pharmaceutical preparations.

[001968] Additional pharmaceutical excipients and carriers that may be used in the pharmaceuticals described in this document are listed in various manuals (e.g. DE Bugay and WP Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, New York, 1999) ), EM Hoepfner, A. Reng and PC Schmidt (Eds) Fiedler

Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas (Cantor Edition, Munich, 2002) and H. P. Fielder (Ed) Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete (Cantor Aulendorf Edition, 1989)).

[001969] In some embodiments, each of one or more pharmaceutically acceptable excipients may be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhancers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizing agents, antioxidants, wetting or emulsifying agents, suspending agents, pigments, dyes, isotonic agents, chelating agents, emulsifiers and diagnostic agents.

[001970] In certain embodiments, each of one or more pharmaceutically acceptable excipients may be independently selected from thickeners, viscosity enhancing agents, mucoadhesive agents, buffers, preservatives, diluents, binders, lubricants, sliders, disintegrators and loads.

[001971] In certain embodiments, each of one or more pharmaceutically acceptable excipients may be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffers, preservatives, and fillers. .

[001972] In certain embodiments, each of the one or more pharmaceutically acceptable excipients may be independently selected from among diluents, binders, lubricants, glidants and disintegrants.

[001973] Examples of thickeners, viscosity-increasing agents and mucoadhesive agents include, without limitation: gums, e.g. xanthan gum, guar gum, locust bean gum, tragacanth gum, karaya gum, ghatti gum, chola gum , psyllium seed gum and gum arabic; Poly(carboxylic acid-containing) based polymers, such as poly(acrylic, maleic, itaconic, citraconic, hydroxyethylmethacrylic or methacrylic acid) that have strong hydrogen-bonding groups or derivatives thereof, such as salts and esters; cellulose derivatives such as methylcellulose, ethylcellulose, methylethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose or esters or ethers of cellulose or derivatives or salts thereof; clays, such as manomorillonite clays, for example Veegun, attapulgite clay; polysaccharides such as dextran, pectin, amylopectin, agar, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan, for example lactate or glutamate or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metals or water-soluble salts of alginic acid, such as sodium alginate or magnesium alginate; scleroglucan; adhesives containing bismuth oxide or aluminum oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinyl chlorides, polyvinylidenes and/or the like; polycarboxylated vinyl polymers, such as polyacrylic acid, as mentioned above; polysiloxanes; polyethers; polyethylene oxides and glycols; polyalkoxys and polyacrylamides and derivatives and salts thereof.

Preferred examples may include cellulose derivatives such as methylcellulose, ethylcellulose, methylethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose or cellulose esters or ethers or derivatives or salts thereof (e.g. methylcellulose) ; and polyvinyl polymers, such as polyvinylpyrrolidone (povidone).

[001974] Examples of preservatives include, without limitation: benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphene bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, ethyl phenyl alcohol, chlorhexidine, polyaxamethylene biguanide, sodium perborate, imidazolidinylurea, sorbic acid, Purite®), Polyquart®) and sodium perborate tetrahydrate and the like.

[001975] In certain embodiments, the preservative is a paraben or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl substituted 4-hydroxybenzoate or a pharmaceutically acceptable ester or salt thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methyl paraben), or the pharmaceutically acceptable ester or salt thereof, propyl 4-hydroxybenzoate (propyl paraben), or the pharmaceutically acceptable ester or salt thereof, or a combination thereof .

[001976] Examples of buffers include without limitation: phosphate buffer system (dehydrated sodium dihydrogen phosphate, disodium phosphate dodecahydrate, dibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer system and of bisulfate buffer.

[001977] Examples of disintegrators include without limitation: calcium carmellose, low substituted hydroxypropylcellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, sodium carboxymethyl starch, crospovidone, polysorbate 80 (polyoxyethylene sorbitan oleate ), starch, sodium starch glycollate, pregelatinized hydroxypropyl cellulose starch, clays, cellulose

lose, alginine, gums or cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp). In certain embodiments, the disintegrant is crospovidone.

[001978] Examples of anti-sticking agents and lubricants (aggregation inhibitors) include, without limitation: talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes, hydrogenated oil, polyethylene glycol, sodium benzoate, stearic acid, glycerol behenate, polyethylene glycol and mineral oil. In certain embodiments, the anti-stick/lubricant agent is magnesium stearate, talc and/or colloidal silica; for example magnesium stearate and/or talc.

[001979] Examples of diluents, also called "fillers" or "bulking agents", include, without limitation: dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g. lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).

[001980] Examples of binders include, without limitation: starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums, such as acacia tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose and veegum and synthetic polymers, such as copolymers of acrylic acid and methacrylic acid, copolymers of methacrylic acid, copolymers of methyl methacrylate, copolymers of aminoalkyl methacrylate, copolymers of aminoalkyl methacrylate, copolymers of amino-

alkyl methacrylate, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).

[001981] In some embodiments, enema formulations containing the chemical entities described herein include water and one or more (e.g., all) of the following excipients:  One or more (e.g., one, two, or three ) thickeners, viscosity increasing agents, binders and/or mucoadhesive agents (e.g. cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g. methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone);  One or more (e.g. one or two; e.g. two) preservatives, such as a paraben, e.g. methyl 4-hydroxybenzoate (methylparaben) or a pharmaceutically acceptable salt or ester of the same, propyl 4-hydroxybenzoate (propyl paraben) or a pharmaceutically acceptable salt or ester thereof, or a combination thereof;  One or more (e.g. one or two; e.g. two) buffers, such as phosphate buffer system (e.g. dihydrogen phospho dehydrated sodium act, disodium phosphate dodecahydrate);  One or more (e.g. one or two, e.g. two) anti-sticking and/or lubricating agents, such as magnesium stearate and/or talc;  One or more (eg one or two; eg one) disintegrators, such as crospovidone; and  One or more (e.g. one or two; e.g. one) diluents, such as lactose (e.g. lactose monohydrate).

[001982] In certain such embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof.

[001983] In certain embodiments, enema formulations containing the chemical entities described herein include water, methylcellulose, povidone, methylparaben, propylparaben, dehydrated sodium dihydrogen phosphate, disodium phosphate dodecahydrate, crospovidone, lactose monohydrate. hydrated, magnesium stearate and talc. In certain such embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof.

[001984] In certain embodiments, enema formulations containing the chemical entities described herein are provided in one or more kits or packages. In certain embodiments, the kit or package includes two separately contained/packaged components, which, when mixed together, provide the desired formulation (eg, as a suspension). In certain such embodiments, the two-component system includes a first component and a second component, wherein: (i) the first component (e.g., contained in a sachet) includes the chemical entity (as described elsewhere herein ) and one or more pharmaceutically acceptable excipients (eg formulated together as a solid preparation, eg formulated together as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and one or more other pharmaceutically acceptable excipients which together form a liquid carrier. In other embodiments, each of components (i) and (ii) is provided in its own separate kit or package.

[001985] In certain such embodiments, component (i) includes the chemical entity (e.g., a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof;

e.g. a compound of Formula AA) and one or more (e.g. all) of the following excipients: (a) one or more (e.g. one) binders (e.g. a polyvinyl polymer such as such as polyvinylpyrrolidone (povidone); (b) one or more (e.g. one or two, e.g. two) anti-sticking and/or lubricating agents, such as magnesium stearate and/or talc; (c) one or more (e.g. e.g. one or two; e.g. one) disintegrants such as crospovidone; and (d) one or more (e.g. one or two; e.g. one) diluents such as lactose (e.g. lactose).

[001986] In certain embodiments, component (i) includes from about 40 weight percent to about 80 weight percent (e.g., from about 50 weight percent to about 70 weight percent, from about 55 weight percent to about 70 weight percent; from about 60 weight percent to about 65 weight percent; for example, about 62.1 weight percent) of the chemical entity (for example, a compound of Formula AA, or a pharmaceutically acceptable salt and/or a hydrate and/or cocrystal thereof).

[001987] In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 1.5 weight percent to about 4, 5 weight percent, from about 2 weight percent to about 3.5 weight percent; for example, about 2.76 weight percent) of the binder (e.g., povidone).

[001988] In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent). weight percent, from about 1 weight percent to about 3 weight percent; about 2 weight percent, e.g., about 1.9 weight percent)

of the disintegrator (eg crospovidone).

[001989] In certain embodiments, component (i) includes from about 10 weight percent to about 50 weight percent (e.g., from about 20 weight percent to about 40 weight percent, from about 25 weight percent to about 35 weight percent, for example about 31.03 weight percent) of the diluent (e.g. lactose, e.g. lactose monohydrate).

[001990] In certain embodiments, component (i) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent). percent by weight) of the anti-sticking agents and/or lubricants.

[001991] In certain embodiments (e.g., when component (i) includes one or more lubricants, such as magnesium stearate), component (i) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 1 weight percent; from about 0.1 weight percent to about 1 weight percent; from about 0.1 weight percent to about 0.5 weight percent; for example, about 0.27 weight percent) of the lubricant (e.g., magnesium stearate).

[001992] In certain embodiments (when component (i) includes one or more lubricants, such as talc), component (i) includes from about 0.5 weight percent to about 5 weight percent (per for example, from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; from about 1.5 weight percent by weight to about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight percent; about 1.93 weight percent) of the lubricant (e.g., baby powder).

[001993] In certain of these embodiments, each of (a), (b), (c) and (d) above is present.

[001994] In certain embodiments, component (i) includes the ingredients

entities and quantities as shown in Table A.

Table A Ingredient Percent by weight Formula Composite - 40 percent by weight to about 80 percent by weight AA mula (e.g., from about 50 percent by weight to about 70 percent by weight, from about 55 weight percent to about 70 weight percent; from about 60 weight percent to about 65 weight percent; for example, about 62.1 weight percent) Crospovidone ( Kolli (0.5 weight percent to about 5 weight percent don CL) by weight (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent weight to about 3 weight percent; about 1.93 weight percent lactate monohydrate; about 10 weight percent to about 50 weight percent (Pharmatose weight percent (e.g., from about 200M) 20 weight percent to about 40 weight percent, from about 25 weight percent to about 35 weight percent; for example, about 31.03 weight percent Povidone (Kollidon ca. 0.5 percent by weight at about 5 K3 0) weight percent (e.g., from about 1.5 weight percent to about 4.5 weight percent, from about 2 weight percent to about 3.5 weight percent; for example, about 2.76 percent by weight

Ingredient Weight percent talc 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent by weight to about 3 weight percent; from about 1.5 weight percent to about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight percent by weight; for example, about 1.93 weight percent magnesium stearate from about 0.05 weight percent to about 1 weight percent (for example, from about 0.05 weight percent weight to about 1 weight percent, from about 0.1 weight percent to about 1 weight percent, from about 0.1 weight percent to about 0.5 weight percent; for example about 0.27 percent by weight

[001995] In certain embodiments, component (i) includes the ingredients and amounts as shown in Table B. Table B Ingredient Percent by weight Compound of Formula AA about 62.1 percent by weight) Crospovidone (Kollidon CL ) about 1.93 weight percent lactose monohydrate (Pharma- about 31.03 weight percent tose 200M) Povidone (Kollidon K30) about 2.76 weight percent talc about 1.93 weight percent magnesium stearate about 0.27 weight percent

[001996] In certain embodiments, component (i) is formulated as a wet granulated solid preparation. In certain of these embodiments, an internal phase of ingredients (the chemical entity, the disintegrator and the diluent) are combined and mixed in a high shear granulator. A binder (e.g. povidone) is distributed

dissolved in water to form a granulation solution. This solution is added to the Internal Phase mixture resulting in the development of granules. Without being bound by theory, it is believed that granule development is facilitated by the interaction of the polymeric binder with the materials of the internal phase. Once the granulation is formed and dried, an external phase (eg one or more lubricants - not an intrinsic component of the dry granulation) is added to the dry granulation. Lubrication of the granulation is believed to be important for the fluidity of the granulation, in particular for packaging.

[001997] In certain foregoing embodiments, component (ii) includes water and one or more (e.g. all) of the following excipients: (a') one or more (e.g. one, two; e.g. two) thickeners , viscosity enhancing agents, binders and/or mucoadhesive agents (e.g. cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g. methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone) (b') one or more (e.g. one or two; e.g. two) preservatives, such as a paraben, e.g. methyl 4-hydroxybenzoate (methylparaben), or the ester or pharmaceutically acceptable salt of the same, propyl 4-hydroxybenzoate (propyl paraben), or the ester or pharmaceutically acceptable salt thereof, or a combination thereof; and (c') one or more (e.g. one or two; e.g. two) buffers, such as a phosphate buffer system (e.g. sodium dihydrogen phosphate dihydrate, disodium phosphate dodeca-hydrated hate);

[001998] In certain foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients: (a'') a first thickener, viscosity enhancing agent, binder

dye and/or mucoadhesive agent (for example a cellulose or cellulose ester or ester or derivative or salt thereof (for example methyl cellulose)); (a''') a second thickening agent, viscosity enhancing agent, binder and/or mucoadhesive agent (e.g. a polyvinyl polymer such as polyvinylpyrrolidone (povidone)); (b'') a first preservative, such as a paraben, for example, propyl 4-hydroxybenzoate (propyl paraben), or a pharmaceutically acceptable salt or ester thereof; (b'') a second preservative, such as a paraben, for example, methyl 4-hydroxybenzoate (methyl paraben), or a pharmaceutically acceptable salt or ester thereof; (c'') a first buffer, such as a phosphate (eg disodium phosphate dodecahydrate); (c''') a second buffer, such as the phosphate buffer system (eg dehydrated sodium dihydrogen phosphate).

[001999] In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent by weight, from about 0.1 weight percent to about 3 weight percent, for example, about 1.4 weight percent) of (a'').

[002000] In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight percent, for example, about 1.0 weight percent) of (a''').

[002001] In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.1 weight percent (e.g., from about 0.005 weight percent to about 0.05 percent percent by weight; for example, about 0.02 percent by weight) of

(B'').

[002002] In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; for example, about 0.20 weight percent) of (b''').

[002003] In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent, for example about 0.15 weight percent) of (c'').

[002004] In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.5 weight percent (e.g., from about 0.005 weight percent to about 0.3 weight percent; for example, about 0.15 weight percent) of (c''').

[002005] In certain of these modes, each of (a'') to (c''') is present.

[002006] In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table C. Table C Ingredient Percent by weight methyl cellulose (Me- 0.05 percent by weight to about 5 weight percent black A15C (e.g., from about 0.05 mium) weight percent to about 3 weight percent, from about 0.1 weight percent to about of 3 weight percent; for example, about 1.4 weight percent Povidone (Kollidon 0.05 weight percent to about 5 weight percent) (for example, from about 0. 05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight percent; for example, about 1.0 weight percent

Ingredient Weight percent 4-hydroxybenzoate from about 0.005 weight percent to about 0.1 weight percent propyl (e.g., from about 0.005 weight percent to about 0.05 weight percent; for example, about 0.02 weight percent) 4-hydroxybenzoate from about 0.05 weight percent to about 1 weight percent methyl (for example, from about 0.05 weight percent to about 0.5 weight percent; for example, about 0.20 weight percent) disodium phosphate from about 0.05 weight percent to about 1 weight percent decahydrate (for example , from about 0.05 weight percent to about 0.5 weight percent; for example, about 0.15 weight percent) dihydrogen phosphate about 0.005 weight percent to about sodium dihydrate 0.5 weight percent (for example, from about 0.005 weight percent to about 0.3 weight percent; for example, about 0.15 weight percent)

[002007] In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table D. Table D Ingredient Percent by weight methyl cellulose (Methocel A15C about 1.4 percent by premium weight) Povidone (Kollidon K30) about 1.0 weight percent propyl 4-hydroxybenzoate about 0.02 weight percent methyl 4-hydroxybenzoate about 0.20 weight percent disodium dodeca-phosphate 0.15 weight percent hydrated sodium dihydrogen phosphate di- about 0.15 weight percent hydrated

[002008] "Ready-to-use" enemas are generally supplied in a sealed "single-use" disposable plastic or glass container. Those formed of a polymeric material preferably have sufficient flexibility for ease of use by an unattended patient. Typical plastic containers can be produced from polyethylene. Such containers may comprise a tip for direct introduction into the rectum. Such containers may also comprise a tube between the container and the tip. The tip is preferably provided with a protective shield that is removed before use. Optionally, the tip has a lubricant to improve patient adhesion.

[002009] In some embodiments, the enema formulation (eg, suspension) is poured into a bottle for delivery after it has been prepared in a separate container. In certain embodiments, the bottle is a plastic bottle (eg flexible to allow delivery by squeezing the bottle), which may be a polyethylene bottle (eg white in color). In some embodiments, the bottle is a single chamber bottle, which contains the suspension or solution. In other embodiments, the bottle is the multi-chamber bottle, where each chamber contains a separate mixture or solution. In still other embodiments, the bottle may further include a rectal tip or cannula for direct introduction into the rectum. dosages

[002010] Dosages can be varied depending on the patient's need, the severity of the condition being treated and the particular compound that is employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical art. The total daily dosage can be divided and administered in portions throughout the day or by means that provide continuous delivery.

[002011] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg /kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0.1 mg/kg to about 200 mg/kg; from about 0.1 mg/kg to about 150 mg/kg; from about 0.1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about 0.1 mg/kg to about 10 mg/kg; from about 0. 1 mg/kg to about 5 mg/kg; from about 0.1 mg/kg to about 1 mg/kg; from about 0.1 mg/kg to about 0.5 mg/kg).

[002012] In some embodiments, the enema formulations include from about 0.5 mg to about 2,500 mg (e.g., from about 0.5 mg to about 2,000 mg, from about 0.5 mg to about 1000 mg, from about 0.5 mg to about 750 mg, from about 0.5 mg to about 600 mg, from about 0.5 mg to about 500 mg, from about 0. 5 mg to about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg to about 200 mg; for example, from about 5 mg to about 5 mg

2500 mg, from about 5 mg to about 2,000 mg, from about 5 mg to about 1,000 mg; from about 5 mg to about 750 mg; from about 5 mg to about 600 mg; from about 5 mg to about 500 mg; from about 5 mg to about 400 mg; from about 5 mg to about 300 mg; from about 5 mg to about 200 mg; for example, from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 750 mg, from about 50 mg to about 600 mg, from from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 50 mg to about 200 mg; for example from about 100mg to about 2500mg, from about 100mg to about 2000mg, from about 100mg to about 1000mg, from about 100mg to about 750mg, from about 100mg to about 750mg 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg; for example, from about 150 mg to about

2500mg, from about 150mg to about 2000mg, from about 150mg to about 1000mg, from about 150mg to about 750mg, from about 150mg to about 700mg, from about 150mg to about 700mg 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 150 mg to about 200 mg; for example, from about 150 mg to about 500 mg; for example, from about 300 mg to about 2,500 mg, from about 300 mg to about 2,000 mg, from about 300 mg to about

1000 mg, from about 300 mg to about 750 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg; for example, from about 400 mg to about 2,500 mg, from about 400 mg to about 2,000 mg, from about 400 mg to about 1,000 mg, from about 400 mg to about 750 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 from about 400 mg to about 500 mg; e.g. 150 mg or 450 mg) of the chemical entity in from about 1 ml to about 3000 ml (e.g. from about 1 ml to about 2000 ml, from about 1 ml to about 1000 ml, from about 1 ml to about 500 ml, from about 1 ml to about 250 ml, from about 1 ml to about 100 ml, from about 10 ml to about 1000 ml, from about 10 ml to about 500 ml, from about 10 ml to about 250 ml, from about 10 ml to about 100 ml, from about 30 ml to about 90 ml, from about 40 ml to about 80 ml; from about 50 ml to about

70 ml; for example about 1 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, about 50 ml, about 55 ml, about 60 ml, about 65 ml, about 70 ml, about 75 ml, about 100 ml, about 250 ml, or about 500 ml , or about 1000 ml or about 2000 ml or about 3000 ml; eg 60 ml) of liquid carrier.

[002013] In certain embodiments, the enema formulations include from about 50 mg to about 250 mg (e.g., from about 100 mg to about 200; e.g., about 150 mg) of the chemical entity in from about 10 ml to about 100 ml (e.g. from about 20 ml to about 100 ml, from about 30 ml to about 90 ml, from about 40 ml to about 80 ml; from about 40 ml to about 80 ml; from about 30 ml to about 90 ml 50 ml to about 70 ml) of liquid carrier. In certain embodiments, the enema formulations include about 150 mg of the chemical entity in about 60 ml of the liquid carrier. In certain such embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 150 mg of a compound of Formula AA in about 60 ml of the liquid carrier.

[002014] In certain embodiments, the enema formulations include from about 350 mg to about 550 mg (e.g., from about 400 mg to about 500; e.g., about 450 mg) of the chemical entity in from about 10 ml to about 100 ml (e.g. from about 20 ml to about 100 ml, from about 30 ml to about 90 ml, from about 40 ml to about 80 ml; from about 40 ml to about 80 ml; from about 30 ml to about 90 ml 50 ml to about 70 ml) of liquid carrier. In certain embodiments, the enema formulations include about 450 mg of the chemical entity in about 60 ml of the liquid carrier. In certain such embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 450 mg of a compound of Formula AA in about 60 ml of the liquid carrier.

[002015] In some embodiments, enema formulations include from about 0.01 mg/ml to about 50 mg/ml (e.g., from about 0.01 mg/ml to about 0.01 mg/ml). 25 mg/ml; from about 0.01 mg/ml to about 10 mg/ml; from about 0.01 mg/ml to about 5 mg/ml; from about 0.1 mg/ml to about 0.1 mg/ml from 50 mg/ml; from about 0.01 mg/ml to about 25 mg/ml; from about 0.1 mg/ml to about 10 mg/ml; from about 0.1 mg/ml to about 5 mg/ml; from about 1 mg/ml to about 10 mg/ml; from about 1 mg/ml to about 5 mg/ml; from about 5 mg/ml to about 10 mg/ml; for example, about 2.5 mg/ml or about 7.5 mg/ml) of the chemical entity in liquid carrier. In certain such embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 2.5 mg/ml or about 7.5 mg/ml of a compound of Formula AA in liquid carrier. regimes

[002016] The above dosages can be administered daily (e.g. as a single dose or as two or more divided doses) or non-daily (e.g. every other day, every other day, every three days , once a week, twice a week, once every two weeks, once a month).

[002017] In some embodiments, the period of administration of a compound described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months , 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

In another embodiment, a period during which administration is stopped is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months , 8 months, 9 months, 10 months, 11 months, 12 months or more.

In one embodiment, a therapeutic compound is administered to a subject for a period of time followed by a separate period of time.

In another embodiment, a therapeutic compound is administered for a first period and a second period after the first period, with administration interrupted during the second period, followed by a third period in which administration of the therapeutic compound is initiated. and then a fourth period after the third period when administration is interrupted.

In one aspect of this embodiment, the period of administration of a therapeutic compound followed by a period of discontinuation of administration is repeated for a specified or indeterminate period of time.

In another embodiment, an administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days , 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months , 9 months, 10 months, 11 months, 12 months or more.

In another embodiment, a period during which administration is interrupted is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

Treatment Methods

[002018] In some embodiments, methods are provided for treating an individual with a condition, disease, or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder, which comprises administering to a subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). indications

[002019] In some embodiments, the condition, disease, or disorder is selected from: inappropriate host responses to infectious disease, where there is active infection anywhere in the body, such as septic shock, disseminated intravascular coagulation, and/or stroke syndrome. respiratory distress in adults; acute or chronic inflammation due to deposition of antigen, antibody and/or complement; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis, immune-based diseases such as acute and delayed hypersensitivity, graft rejection and disease graft versus host; autoimmune diseases, including type 1 diabetes mellitus and multiple sclerosis. For example, the condition, disease or disorder may be an inflammatory disorder, such as rheumatoid arthritis, osteoarthritis, septic shock, COPD and periodontal disease.

[002020] In some embodiments, the condition, disease or disorder is an autoimmune disease. Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn's disease (CD)

and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy treatment, colitis associated with one or more alloimmune diseases ( such as graft-versus-host disease, eg, acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagen colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis . In some of these modalities, the condition is alloimmune disease (such as graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), celiac disease, irritable bowel syndrome , rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (eg, oral mucositis, esophageal mucositis, or intestinal mucositis).

[002021] In some modalities, the condition, disease, or disorder is selected from among the major adverse cardiovascular events, such as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with a prior heart attack and inflammatory atherosclerosis (See, for example, document No. NCT01327846).

[002022] In some embodiments, the condition, disease, or disorder is selected from metabolic disorders, such as type 2 diabetes, atherosclerosis, obesity, and gout, in addition to central nervous system diseases, such as Alzheimer's disease and multiple sclerosis, and Sclerosclerosis. if Lateral Amyotrophic and Parkinson's disease, lung disease such as asthma and COPD and idiopathic pulmonary fibrosis, liver disease such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease

ca, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease, such as Crohn's disease and Ulcerative Colitis, skin diseases, such as psoriasis, musculoskeletal diseases, such as scleroderma, disorders of vessels such as giant cell arteritis, bone disorders such as Osteoarthritis, osteoporosis and osteopetrosis disorders, eye disease such as glaucoma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune diseases , such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.

[002023] In some embodiments, the condition, disease or disorder is a cardiovascular indication. In some embodiments, the condition, disease, or disorder is myocardial infarction. In some embodiments, the condition, disease, or disorder is stroke.

[002024] In some embodiments, the condition, disease or disorder is obesity.

[002025] In some embodiments, the condition, disease, or disorder is Type 2 Diabetes.

[002026] In some embodiments, the condition, disease, or disorder is NASH.

[002027] In some embodiments, the condition, disease or disorder is Alzheimer's disease.

[002028] In some embodiments, the condition, disease or disorder is gout.

[002029] In some embodiments, the condition, disease, or disorder is SLE.

[002030] In some embodiments, the condition, disease, or disorder is rheumatoid arthritis.

[002031] In some embodiments, the condition, disease, or disorder is IBD.

[002032] In some embodiments, the condition, disease, or disorder is multiple sclerosis.

[002033] In some embodiments, the condition, disease, or disorder is COPD.

[002034] In some embodiments, the condition, disease or disorder is asthma.

[002035] In some embodiments, the condition, disease, or disorder is scleroderma.

[002036] In some embodiments, the condition, disease, or disorder is pulmonary fibrosis.

[002037] In some embodiments, the condition, disease, or disorder is age-related macular degeneration (AMD).

[002038] In some embodiments, the condition, disease, or disorder is cystic fibrosis.

[002039] In some embodiments, the condition, disease or disorder is Muckle Wells syndrome.

[002040] In some embodiments, the condition, disease, or disorder is familial cold-associated autoinflammatory syndrome (FCAS).

[002041] In some embodiments, the condition, disease, or disorder is chronic neurological cutaneous and joint syndrome.

[002042] In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying NLRP3 mutation or overexpression; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoid treatment; Langerhan cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML); chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis.

[002043] In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying NLRP3 mutation or overexpression; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoid treatment; Langerhan cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; gastric cancer; and lung cancer metastasis.

[002044] In some modalities, the indication is MDS.

[002045] In some modalities, the indication is non-small lung cancers in patients carrying NLRP3 mutation or overexpression.

[002046] In some modalities, the indication is ALL in patients resistant to glucocorticoid treatment.

[002047] In some embodiments, the indication is LCH.

[002048] In some modalities, the indication is multiple myeloma.

[002049] In some modalities, the indication is promyelocytic leukemia.

[002050] In some modalities, the indication is gastric cancer.

[002051] In some modalities, the indication is lung cancer metastasis. combination therapy

[002052] This disclosure contemplates both monotherapy regimens and combination therapy regimens.

[002053] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with traction of the compounds described herein.

[002054] In certain embodiments, the second agent or therapeutic regimen is administered to the subject prior to contact or administration of the chemical entity (e.g., about one hour before, or about 6 hours before, or about 12 hours before , or about 24 hours before, or about 48 hours before, or about 1 week before, or about 1 month before).

[002055] In other embodiments, the second therapeutic agent or regimen is administered to the individual at about the same time as contact with or administration of the chemical entity. By way of example, the second agent or therapeutic regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in separate dosage forms.

[002056] In still other embodiments, the second agent or therapeutic regimen is administered to the subject after contact or administration of the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after). Patient Selection

[002057] In some embodiments, the methods described in this document further include the step to identify an individual (e.g., a patient) who needs treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 activity. to the NLRP3 polymorphism.

[002058] In some embodiments, the methods described in this document further include the step of identifying an individual (e.g., a patient) who needs treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 activity. to NLRP3, where the polymorphism is a gain of function.

[002059] In some embodiments, the methods described in the present

This document further includes the step of identifying an individual (eg, a patient) who needs treatment for an indication related to NLRP3 activity, such as an indication related to the NLRP3 polymorphism found in CAPS syndromes.

[002060] In some embodiments, the methods described in this document further include the step of identifying an individual (e.g., a patient) who needs treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 activity. with the NLRP3 polymorphism where the polymorphism is VAR_014104 (R262W).

[002061] In some embodiments, the methods described in this document further include the step of identifying an individual (e.g., a patient) who needs treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 activity. with the NLRP3 polymorphism where the polymorphism is a natural variant reported at http://www.uniprot.org/uniprot/Q96P20.

[002062] In some embodiments, the methods described in this document further include the step of identifying an individual (e.g., a patient) who needs treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 activity. to the point mutation of NLRP3 signaling. Preparation of Compounds and Biological Assays

[002063] As will be appreciated by one skilled in the art, methods for synthesizing compounds of the formulas herein will be apparent to those skilled in the art. Synthetic chemical transformations and protecting group (protection and deprotection) methodologies useful in the synthesis of the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). ); T.W. Greene and RGM.

Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. Preparative Examples

[002064] The following abbreviations have the meanings indicated: ACN = acetonitrile Ac = acetyl (BnS)2 = 1,2-dibenzyldisulfan BTC = trichloromethyl chloroformate Boc = t-butyloxycarbonyl Burgess reagent = 1-Methoxy-N-triethylammoniosulfonyl- methanimidate CDI = N,N'-carbonyldiimidazole m-CPBA = 3-chloroperbenzoic acid DAST = diethylaminosulfurtrifluoride DCM = dichloromethane DEA = diethylamine DMAP = N,N-dimethylpyridin-4-amine DME = 1,2-dimethoxyethane DMF = N, N-dimethylformamide DMSO = dimethyl sulfoxide DIEA = N,N-diisopropylethylamine DPPA = diphenylphosphoryl azide EtOH = ethanol EtOAc = ethyl acetate HATU = 2-(3H-[1,2,3]triazolo[4,5 hexafluorophosphate -b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium (V) Hex = hexane HPLC = high performance liquid chromatography

KHMDS = potassium bis(trimethylsilyl)amide LC-MS = liquid chromatography coupled to mass spectrometry LiHMDS = lithium bis(trimethylsilyl)amide LDA = lithium diisopropylamide Me = methyl MeOH = methanol MSA = methanesulfonic acid Mts-S, R, R -Aux = (2R,3aS,8aR)-3-(mesitylsulfonyl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole NBS = N -bromosuccinimide NCS = N-chlorosuccinimide NMP = 1-methylpyrrolidin-2-one NMR= nuclear magnetic resonance Pd(dppf)Cl2 = dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium Pd(dtbpf)Cl2 = [1, 1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) PE = petroleum ether Ph = phenyl PPh3Cl2 = dichlorotriphenylphosphorane Py = pyridine RT = room temperature Rt = retention time RuPhos = 2-dicyclohexylphosphino-2' ,6'-di-i-propoxy-1,1'-biphenyl Sat. = saturated SEM-Cl = (2-(chloromethoxy)ethyl)trimethylsilane TBAF = tetrabutylammonium fluoride TBS = tert-butyldimethylsilyl TBSCl = tert-butyldimethylsilyl chloride TBDPSCl = tert-butyl chloride iphenylsilyl t-BuOK = potassium 2-methylpropan-2-olate t-BuOLi = lithium 2-methylpropan-2-olate

TCCA = trichloroisocyanuric acid TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMAD = (E)-N1,N1,N2,N2-tetramethyldiazene-1,2-dicarboxamide TsOH = 4-methylbenzenesulfonic acid UV = ultraviolet Xphos Pd G2 = chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ]palladium(II) DMA = dimethylacetamide Davephos = 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl KHMDS = potassium bis(trimethylsilyl)amide KF = Kart Fischer NMO = 4-Methylmorpholine N-oxide Pd( dtbpf)Cl2 = 1,1'-Bis(di-t-butylphosphino)ferrocene palladium chloride Phos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TLC = thin layer chromatography T3P = 2,4,6- 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatryphosphine trioxide General

[002065] The progress of the reactions was often monitored by TLC or LC-MS. The identity of the products was frequently confirmed by LC-MS. The LC-MS was recorded using one of the following methods.

[002066] Method A: Shim-pack XR-ODS, C18, 3x50 mm, 2.5 um column, 1.0 ul injection, flow rate 1.5 ml/min, scanning range 90 to 900 amu , UV range 190 to 400 nm, 5 to 100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA ), total round time 2 minutes.

[002067] Method B: Kinetex EVO, C18, 3x50 mm, 2.2 um column,

1.0 ul injection, 1.5 ml/min flow rate, 90 to 900 amu scanning range, 190 to 400 nm UV range, 10 to 95% (1.1 min), 95% ( 0.6 min) gradient with ACN and water (0.5% NH4HCO3), total run time 2 min.

[002068] Method C: Shim-pack XR-ODS, C18, 3x50 mm, 2.5 um column, 1.0 ul injection, 1.5 ml/min flow rate, 90 scan range at 900 amu, UV range 190 to 400 nm, 5 to 100% (2.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05 % TFA), total round time 3 minutes.

[002069] Method D: Kinetex EVO, C18, 3x50 mm, 2.2 um column, 1.0 ul injection, 1.5 ml/min flow rate, 90 to 900 amu scanning range, UV 190 to 400 nm, 10 to 95% (2.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH4HCO3), total run time 3 minutes.

[002070] Method F: Phenomenex, CH0-7644, Onyx Monolithic C18, 50 x 4.6 mm, 10.0 ul injection, 1.5 ml/min flow rate, 100 to 1500 amu scan range, UV detection at 220 and 254 nm, 5% with ACN (0.1% TFA) in 100% water (0.1% TFA) for 9.5 min, with a dwell at 100% (ACN, 0 .1% TFA) for 1 min, then equilibrate at 5% (ACN, 0.1% TFA) for 1.5 min.

[002071] Final targets were purified by preparatory HPLC. Preparatory HPLC was performed using the following method.

[002072] Method E: Preparatory HPLC: Column, XBridge Shield RP18 OBD (19x250 mm, 10 µm); mobile phase, Water (10 mM NH4HCO3) and ACN, UV detection 254/210 nm.

[002073] Method G: Preparatory HPLC: Higgins Analytical Proto 200, Column C18, 250 x 20 mm, 10 µm; mobile phase, Water (0.1% TFA) and ACN (0.1% TFA), UV detection 254/210 nm.

[002074] The NMR was registered in BRUKER NMR 300.03 MHz, DUL-C-H, ULTRASHIELDTM300, AVANCE II 300 B-ACSTM120 or BRUKER

NMR 400.13 MHz, BBFO, ULTRASHIELDTM400, AVANCE III 400, B-ACSTM120

[002075] Scheme for End Targets: Schemes 1 through 7 below illustrate various conditions used for coupling sulfonimidamide and isocyanate to provide aminocarbonyl sulfonimidamide. Scheme 1: Scheme 1A: Scheme 2: Scheme 2A:

Scheme 2B:

Scheme 3:

Scheme 3A:

Scheme 4:

Scheme 4A:

Scheme 5:

Scheme 6:

Scheme 7:

Scheme I:

Scheme II:

Scheme III:

Scheme IV: Scheme V: Scheme VI: Scheme VII: Scheme VIII:

[002076] Scheme for End Targets: Schemes IX through XVI below illustrate various conditions used for coupling sulfonimide and isocyanate to provide aminocarbonyl sulphonimidamide.

Scheme IX:

Scheme X:

Scheme XI:

Scheme XII:

Scheme XIII:

Schedule XIV: Schedule XV: Schedule XVI:

[002077] Scheme for Preparing Sulfonamide Intermediates: Schemes 8A to 28 below illustrate the preparation of sulfonamide intermediates.

Scheme 8A: Intermediate 1

TBS H2N N

S S THE oh

N N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Step 1: 1-(thiazol-2-yl)ethanol

[002078] In a 500 ml round bottom flask was placed 1-(thiazol-2-yl)ethanone (20 g, 157 mmol) in EtOH (200 ml). This was followed by the addition of NaBH4 (3.0 g, 81.3 mmol) in portions at 0 °C. The resulting solution was stirred for 2 h at RT and then quenched by the addition of 10 ml of NH4Cl (sat.). The resulting solution was diluted with 200 ml of water and extracted with 2x200 ml of DCM. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. This resulted in 20 g (98%) of the title compound as a pale yellow oil. MS-ESI: 130 (M+1). Step 2: 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole

[002079] In a 500 ml round bottom flask was placed 1-(thiazol-2-yl)ethanol (20 g, 155 mmol) in DMF (150 ml). To the stirred solution

Then, 1H-imidazole (20.5 g, 301 mmol) was added. This was followed by the addition of TBDPSCl (46 g, 167 mmol) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at RT and then diluted with 300 ml of water. The resulting solution was extracted with 3x200 ml of DCM. The organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:100 to 1:80). This resulted in 55 g (97%) of the title compound as a colorless oil. MS-ESI: 368.1 (M+1). Step 3: 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazol-5-sulfonyl chloride

[002080] In a 500 ml 3-necked round bottom flask, purged with and maintained under nitrogen, a solution of 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (30 g, 81.6 mmol) in THF (200 ml). This was followed by the addition of n-BuLi (2.5M in THF, 35.2 ml) drip with stirring at -78°C. The resulting solution was stirred for 0.5 h at -78 °C and then SO 2 was introduced into the above reaction mixture. The reaction was slowly warmed to RT and then NCS (12.8 g, 95.9 mmol) was added. The resulting solution was stirred for 1 h at RT. Solids were removed by filtration. The resulting filtrate was concentrated in vacuo. This resulted in 30 g (crude product, 79%) of the title compound as a brown oil. The crude product was used in the next step. Step 4: N-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazol-5-sulfonamide

[002081] In a 500 ml round bottom flask was placed 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazol-5-sulfonyl chloride (crude product, 30 g, 64.4 mmol) in DCM (200 ml). To the stirred solution, TEA (13 g, 128 mmol) was added dropwise. This was followed by the addition of 2-methylpropan-2-amine (5.6 g, 76.6 mmol) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at RT and then

was concentrated under vacuum. The residue was eluted from silica gel with an EtOAc/PE gradient (1:30 to 1:20). This resulted in 25 g (61% over two steps) of the title compound as a brown oil. MS-ESI: 503.2 (M+1). Step 5: N-tert-butyl-2-(1-hydroxyethyl)thiazol-5-sulfonamide

[002082] In a 500 ml round bottom flask was placed N-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonamide (25 g, 49.7 mmol) in THF ( 200 ml). To this stirred solution, TBAF (30 g, 99.7 mmol) was added in portions. The resulting solution was stirred for 2 h at RT and then diluted with 200 ml of water. The resulting solution was extracted with 3x200 ml of DCM acetate. The organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:20 to 1:10). This resulted in 12 g (91%) of the title compound as a pale yellow oil. MS-ESI: 265.1 (M+1). Step 6: 2-Acetyl-N-tert-butylthiazole-5-sulfonamide

[002083] In a 500 ml round bottom flask was placed N-tert-butyl-2-(1-hydroxyethyl)thiazol-5-sulfonamide (12 g, 45.4 mmol) in DCM (200 ml). To this solution, Dess-Martin reagent (20 g, 47.2 mmol) was added in portions with stirring at RT. The resulting solution was stirred for 2 h at RT and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:20 to 1:10). This resulted in 9.0 g (76%) of the title compound as a pale yellow solid. MS-ESI: 263.0 (M+1). Step 7: 2-Acetylthiazole-5-sulfonamide

[002084] In a 100 ml round bottom flask, 2-Acetyl-N-tert-butylthiazole-5-sulfonamide (7.0 g, 26.7 mmol) in TFA (20 ml) was placed. The resulting solution was stirred for 14 h at 70 °C and then concentrated under vacuum. The residue was eluted from silica gel with an EtOAc/PE gradient (1:5 to 1:3). This resulted in 5.0 g (91%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1). Step 8: 2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002085] In a 500 ml 3-necked round bottom flask purged with and maintained under nitrogen was placed 2-acetylthiazol-5-sulfonamide (5.0 g, 24.3 mmol) in THF (100 ml). This was followed by the addition of MeMgBr (3M in THF, 8.1 ml, 24.3 mmol) dropwise with stirring at 0°C. The resulting solution was stirred for 14 h at RT and then quenched by the addition of 100 ml of NH4Cl (sat.). The resulting solution was extracted with 2x150 ml of DCM acetate. The organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with an EtO-Ac/PE gradient (1:5 to 1:3). This resulted in 2.9 g (54%) of the title compound as a pale yellow solid. MS-ESI: 223.0 (M+1). Step 9: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002086] In a 250 ml round bottom flask purged with and maintained under nitrogen, was placed 2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide (1.0 g, 4.5 mmol) in DCM (100ml). To the stirred solution, 1H-imidazole (613 mg, 9.01 mmol) and TBSCl (3.4 g, 22.5 mmol) were added. The resulting solution was stirred for 14 h at RT and then diluted with 100 ml of water. The resulting mixture was extracted with 3x50 ml of DCM, and the organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with an EtO-Ac/PE gradient (1:10 to 1:3). This resulted in 1.4 g (93%) of the title compound as a white solid. MS-ESI: 337 (M+1). Step 10: N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002087] In a 250 ml 3-necked round bottom flask purged with and maintained under nitrogen, PPh3Cl2 (3.0 g, 10.2 mmol) was placed in CHCl3 (100 ml). This was followed by the addition of TEA

(2.06 g, 20.4 mmol) by drip with stirring at RT. After stirring at 0°C for 10 min, a solution of N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide (2.3 g, 6.8 mmol) in CHCl3 (10 ml) was added to the above with stirring at 0°C. The resulting solution was allowed to react for 30 min at 0°C. To the mixture, a saturated solution of ammonia in DCM (10 ml) was added at 0°C. the resulting solution was stirred for 2 h at RT. The reaction was then stopped with the addition of 100 ml of water. The resulting solution was extracted with 3x50 ml of DCM, and the organic layers combined and concentrated in vacuo. The residue was eluted from silica gel with an EtO-Ac/PE gradient (1:10 to 1:3). This resulted in 1.2 g (53%) of the title compound as a pale yellow solid. MS-ESI: 336 (M+1). Scheme 8B: Intermediate 1

TBS H2N N

S S THE oh

N N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazol

[002088] In a 500 ml round bottom flask, a solution of 1-(thiazol-2-yl)ethanone (20 g, 157 mmol) in toluene (300 ml) and ethane-1,2-diol ( 19.5 g, 314 mmol). To the solution was added

TsOH (2.7 g, 15.7 mmol). The resulting solution was refluxed overnight, and water was separated from the solution during reflux. The resulting solution was diluted with 200 ml of water and extracted with 2x100 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. This resulted in 26.6 g (99%) of the title compound as a pale yellow oil. MS-ESI: 172.0 (M+1). Step 2: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazol-5-sulfonamide

[002089] In a 500 ml 3-necked round bottom flask, purged with and maintained under nitrogen, a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole (14 g, 81 .6 mmol) in THF (200 ml). This was followed by the addition of n-BuLi (2.5M in THF, 35.2 ml, 88 mmol) dropwise with stirring at -78°C. The resulting solution was stirred for 0.5 h at -78 °C and then SO 2 was introduced into the above reaction mixture. The reaction was slowly warmed to RT and then NCS (12.8 g, 95.9 mmol) was added. The resulting solution was stirred for 1 h at RT. Solids were removed by filtration. The resulting filtrate was concentrated in vacuo and then diluted in DCM (160 ml). To the above, a saturated solution of ammonia in DCM (300 ml) was added. The resulting solution was stirred for 3 h at RT and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:20 to 1:5). This resulted in 12.5 g (61%) of the title compound as a yellow solid. MS-ESI: 251.0 (M+1). Step 3: 2-Acetylthiazole-5-sulfonamide

[002090] In a 250 ml round bottom flask, a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazol-5-sulfonamide (12.5 g, 50 mmol) in THF (125 ml). To the above, aqueous HCl (4N, 50.0 ml) was added. The resulting solution was stirred for 6 h at 70 °C. The resulting solution was diluted with 100 ml of water and extracted with 2x200 ml of EtOAc. The organic layers were combined, dried with

Anhydrous Na2SO4 then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:2 to 1:1). This resulted in 9.3 g (90%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1). Step 4: 2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002091] In a 500 ml round bottom flask purged with and maintained under nitrogen, a solution of 2-acetylthiazole-5-sulfonamide (15 g, 72.8 mmol) in THF (150 ml) was placed. This was followed by the addition of MeMgBr (3M in THF, 97 ml, 291 mmol) drip with stirring at 0 °C. The resulting solution was stirred for 14 h at RT and then quenched by the addition of 100 ml of NH4Cl (sat.). The resulting solution was extracted with 3x150 ml of DCM, and the organic layers were combined and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:3). This resulted in 11.5 g (78%) of the title compound as a white solid. MS-ESI: 223 (M+1). Step 5: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002092] A solution of 2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide (5.0 g, 22 .5 mmol) in THF (100 ml). Then, to the above, NaH (60% by weight of oil dispersion, 1.8 g, 45 mmol) was added in portions in an ice/water bath. After stirring for 20 minutes in a water/ice bath, this was followed by the addition of a solution of TBSCl (4.1 g, 27.2 mmol) in THF (10 ml) dropwise with stirring at 0 °C. The resulting solution was stirred for 4 h at RT. The reaction was quenched with saturated NH4Cl (100 ml). The resulting solution was extracted with 3 x 100 ml of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude solid was washed

with EtOAc/hexane (1:5) (2x100 ml). This resulted in 6.81 g (90%) of the title compound as a yellow solid. MS-ESI: 337 (M+1).

[002093] Step 6 used the same procedures to convert compound 20 to Intermediate 1 shown in Scheme 8A to provide Intermediate 1 from compound 25. MS-ESI: 336.1 (M+1). Scheme 9: Intermediate 2

THE

N Y NH2

Y N Boc

HO N'-(tert-butoxycarbonyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Step 1: 2-(Thiazol-2-yl)propan-2-ol

[002094] A solution of 1-(thiazol-2-yl)ethanone (200 g, 1.6 mol) in THF (4 l). This was followed by the addition of MeMgBr (3M in THF, 942 ml) drip with stirring at 0 °C. The mixture was stirred at 0 °C for 2 h. After warming the mixture to RT, the solution was stirred for another 16 h. Then, the reaction was quenched by the addition of 3.0 L of NH4Cl (sat.). The resulting solution was extracted with 3x1 L of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:3 to 1:1). This resulted in 210 g (93%) of the title compound.

home like a brown oil. MS-ESI: 144.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H), 5.94 (s, 1H ), 1.51 (s, 6H). Step 2: Lithium 2-(2-hydroxypropan-2-yl)thiazol-5-sulfinate

[002095] In a 4-neck 10 L round bottom flask purged with and maintained under nitrogen, a solution of 2-(thiazol-2-yl)propan-2-ol (50 g, 349 mmol) in THF was placed (1.5 l). This was followed by the addition of n-BuLi (2.5M in hexane, 350 ml) dropwise with stirring at -78°C. The mixture was stirred at -78 °C for 1 h. Then SO2 was bubbled into the mixture for 15 min below -30 °C. The mixture was stirred for a further 1 h at RT and then concentrated in vacuo. This resulted in 87 g of the title compound as a light yellow solid (crude product). The crude product was used directly in the next step. Step 3: Methyl 2-(2-hydroxypropan-2-yl)thiazol-5-sulfinate

[002096] In a 2 L 3-necked round bottom flask, Lithium 2-(2-hydroxypropan-2-yl)thiazol-5-sulfinate (87 g, crude product) was dissolved in anhydrous methanol (500 ml) . Then, SOCl2 (43 g, 360 mmol) was added to the mixture by drip with stirring at 0 °C. The mixture was stirred overnight at RT and was then concentrated under vacuum. The residue was diluted with 500 ml of EtOAc. The resulting solution was washed with 2x200 ml of water and 2x200 ml of brine. The solution was dried over anhydrous Na2SO4 and then concentrated in vacuo. This resulted in 72 g of the crude title compound as a pale yellow oil. The crude product was used directly in the next step. MS-ESI: 222 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 6.32 (s, 1H), 3.65 (s, 3H), 1.53 (d, J = 2.0 Hz , 6H). Step 4: 2-(2-hydroxypropan-2-yl)thiazol-5-sulfinamide

[002097] In a 10 L 4-necked round bottom flask purged with and maintained under nitrogen, a solution of 2-

Methyl (2-hydroxypropan-2-yl)thiazol-5-sulfinate (72 g, 326 mmol) in THF (500 ml). Then, to the above, NH3 (0.5 M in THF, 2.0 L) was added. After cooling to -78 °C, LiHMDS (1 M in THF, 2.0 L) was added to the mixture by dripping with stirring. Then, the mixture was stirred at -78 °C for 2 h. The reaction was quenched by the addition of 500 ml of NH4Cl (sat.). The resulting solution was extracted with 3x300 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. This resulted in 32 g of the crude title compound as a brown oil. The crude product was used directly in the next step. MS-ESI: 207 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 6.73 (s, 2H), 6.17 (s, 1H), 1.51 (d, J = 1.4 Hz , 6H). Step 5: tert-Butyl 2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate

[002098] A solution of 2-(2-hydroxypropan-2-yl)thiazol-5-sulfinamide (32 g, product crude) in THF (300 ml). This was followed by the addition of LDA (2M in THF, 116 ml) drip with stirring at 0°C. The mixture was stirred at 0 °C for 1 h, then (Boc)2O (33.8 g, 155 mmol) was added in portions at 0 °C. The mixture was warmed to RT and stirred for a further 2 h. The reaction was quenched with 200 ml of ice water (200 ml), and the pH of the solution was adjusted to 6 with HCO2H. The resulting solution was extracted with 3x200 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:2 to 1:1). This resulted in 19 g (18%, 4 steps) of the title compound as a white solid. MS-ESI: 307 (M+1). Step 6: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002099] In a 1 L 3-necked round bottom flask purged with and maintained under nitrogen, tert-Butyl 2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate (19 g, 62 mmol ) was dissolved in fresh distilled ACN (200 ml). Then, to the above solution, NCS (9.8 g, 74 mmol) was added in portions. The mixture was stirred for 1 h at RT and then NH3 was bubbled into the mixture for 15 min. The mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was applied to silica gel and eluted with an EtOAc/PE gradient (1:2 to 1:1). This resulted in 13 g (65%) of the title compound as a white solid. MS-ESI: 322 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.72 (s, 2H), 6.29 (s, 1H), 1.49 (d, J = 2.0 Hz , 6H), 1.27 (s, 9H). Scheme 10: Intermediate 1

TBS H2N N

S S THE oh

N N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Step 1: 2-(2-Hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002100] A solution of tert-butyl 2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidoylcarbamate (3.21 g, 10 mmol) in HCl/ dioxane (4M, 50 ml). The resulting solution was stirred for 1 h at RT. The solution was concentrated to give the title compound (3.2 g, crude, yellow oil). MS-ESI: 222 (M+1). Step 2: N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002101] In a 250 ml round bottom flask, 2-

(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (3.2 g of crude product, 10 mmol) in THF (100 mL), and then DIEA (3.87 g, 30 mmol) was added. in the reaction solution at RT. TBSCl (3.0 g, 20 mmol) was added to the solution in portions. The resulting solution was stirred for 16 h at RT. The solution was concentrated, and the crude product was eluted from silica gel with EtOAc/PE (1:1) to give the title compound (2.3 g, 70% yield, yellow solid). MS-ESI: 336 (M+1). Scheme 11: Intermediate 3 HO H2N

Y N s TBS AT THE

OTBS N'-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Step 1: (2-Bromothiazol-4-yl)methanol

[002102] In a 100 ml round bottom flask was placed a solution of ethyl 2-bromo-1,3-thiazole-4-carboxylate (3.0 g, 12.7 mmol) in EtOH (30 ml) . To the stirred solution, NaBH4 (1.0 g, 25.41 mmol) was added portionwise with an ice/water bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by adding 100 ml of water in an ice/water bath.

The resulting solution was extracted with 3x100 ml of EtOAc and the combined organic layers were concentrated. This resulted in 2.0 g (81%) of the title compound as a yellow oil. MS-ESI: 196.2/194.2 (M+1). Step 2: 2-Bromo-4-((tert-butyldimethylsilyloxy)methyl)thiazole

[002103] In a 100 ml round bottom flask, a solution of (2-bromo-1,3-thiazol-4-yl)methanol (2.0 g, 10.3 mmol) in THF (20 ml ). To the solution, NaH (60% by weight of oil dispersion, 1.2 g, 30.9 mmol) was added in portions with an ice/water bath. After stirring for 15 minutes at RT, a solution of TBSCl (4.7 g, 30.9 mmol) in THF (5 ml) was added dropwise in an ice/water bath. The resulting solution was stirred for 2 h at RT. The reaction was then stopped with the addition of 50 ml of water. The resulting solution was extracted with 3x100 ml of EtOAc, the organic layers were combined, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:30). This resulted in 2.5 g (79%) of the title compound as a yellow oil. MS-ESI: 310.2/308.2 (M+1). Step 3: 2-(4-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)propan-2-ol

[002104] In a 100 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, a solution of 2-bromo-4-((tert-butyldimethylsilyloxy)methyl)thiazole (2.5 g, 8.11 mmol) in THF (30 ml). To this solution, n-BuLi (2.5M in hexane, 4.86 mL, 12.2 mmol) was added dropwise at -78 °C, and the resulting mixture was stirred for 30 min at -78 °C. To the above, acetone (0.9 g, 16.2 mmol) was added dropwise at -78 °C, then stirred for 1 h at RT. The reaction was then stopped with the addition of 100 ml of water. The resulting solution was extracted with 3x100 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE

(1:10). This resulted in 2.0 g (86%) of the title compound as a yellow oil. MS-ESI: 288.2 (M+1). Step 4: 4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonyl chloride

[002105] In a 250 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, a solution of 2-(4-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)propan- 2-ol (2.0 g, 6.96 mmol) in THF (20 ml). To this solution, n-BuLi (2.5M in hexane, 8.4 mL, 20.9 mmol) was added dropwise at -78 °C, and the resulting solution was stirred for 30 min at -78 °C. Then, SO2 was introduced into this solution for 10 min below -30 °C and stirred for 30 min at RT. The resulting solution was concentrated in vacuo. The crude solid was dissolved in DCM (30 ml), followed by addition of NCS (1.4 g, 10.4 mmol) portionwise in an ice/water bath. The solution was stirred for 2 h at RT. The resulting mixture was concentrated in vacuo. This resulted in 2.5 g of the crude title compound as a yellow solid. Step 5: 4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002106] In a 100 ml round bottom flask, a solution of 4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonyl chloride (2, 5 g, 6.48 mmol) in DCM (30 ml). To the above, a saturated solution of ammonia in DCM (10 ml) was added in an ice/water bath. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 1.2 g (51%) of the title compound as a yellow oil. MS-ESI: 367.2 (M+1). Step 6: N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002107] To a solution of 4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide (1.2 g, 3.27 mmol) in THF (20 ml ), NaH (60% by weight of oil dispersion, 0.4 g, 9.8 mmol) was added in portions with an ice/water bath. After stirring for 15 minutes at RT, a solution of TBSCl (1.5 g, 9.82 mmol) in THF (5 ml) was added dropwise in an ice/water bath. The resulting solution was stirred for 2 h at RT. The reaction was quenched by the addition of 100 ml of water. The resulting solution was extracted with 3x100 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 1.3 g (83%) of the title compound as a yellow oil. MS-ESI: 481.2 (M+1). Step 7: N'-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002108] In a 100 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, a solution of PPh3Cl2 (1.4 g, 4.06 mmol) in CHCl3 (10 ml) was placed. TEA (0.80 g, 8.11 mmol) was then added dropwise into an ice/water bath. The solution was stirred at RT for 20 minutes. To that solution was added N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide (1.3 g, 2.70 mmol) in CHCl3 (10 ml) by dropping into an ice/water bath. The solution was stirred for 0.5 h at RT. A saturated solution of ammonia in DCM (20 ml) was poured into this solution at 0 °C. The solution was stirred for 1 h at RT. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 600 mg (46%) of the title compound as a yellow solid. MS-ESI: 480.2 (M+1).

Scheme 12: Intermediate 4 N-(tert-butyldimethylsilyl)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Step 1: 2- Methyl (2-aminothiazol-4-yl)acetate

[002109] In a 1 L round bottom flask, a solution of methyl 4-chloro-3-oxobutanoate (15.0 g, 100 mmol) in EtOH (350 mL) was placed. Then, thiourea (7.6 g, 100 mmol) was added to the solution. The resulting solution was stirred overnight under reflux. The resulting mixture was cooled to RT and filtered to collect the solid. The solid thus obtained was washed with Et 2 O (2x200 ml) and dried in an oven at 50 °C overnight to give the title compound (15.4 g, 89.5%) as a yellow solid. MS-ESI: 173 (M+1). Step 2: Methyl 2-(2-bromothiazol-4-yl)acetate

[002110] In a 500 ml round bottom flask, a solution of methyl 2-(2-aminothiazol-4-yl)acetate (15.4 g, 89.5 mmol) in MeCN (250 ml) was placed. CuBr was added to the solution, followed by t-BuONO, which was added dropwise at 0 °C. The resulting solution was stirred for 30 min at RT and then stirred for 2 h at 70 °C. The resulting mixture was concentrated and eluted from silica gel with EtO-Ac/PE (1:10) to give the title compound (12.3 g, 58.2%) as a white solid. MS-ESI: 236/238 (M+1). Step 3: 2-(2-Bromothiazol-4-yl)ethanol

[002111] In a 1 L round bottom flask, a solution of methyl 2-(2-bromothiazol-4-yl)acetate (12.3 g, 51.9 mmol) in EtOH (200 ml) was placed. NaBH4 (3.9 g, 104 mmol) was added to the solution in portions at 0 °C. The resulting solution was stirred for 3 h at RT. The reaction was then stopped with the addition of 1 L of ice water. The resulting solution was extracted with 3 x 500 ml of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. This resulted in 8.9 g (82.1%) of the title compound as a yellow oil. MS-ESI: 208/210 (M+1). Step 4: 2-Bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)thiazole

[002112] In a 500 ml round bottom flask, a solution of 2-(2-bromothiazol-4-yl)ethanol (8.9 g, 42.6 mmol) in THF (400 ml) was placed. NaH (60% by weight of oil dispersion, 2.56 g, 63.9 mmol) was added to the mixture in portions at 0°C. The mixture was stirred at 0 °C for a further 1 h, and TBSCl (10.2 g, 68.2 mmol) was added to the mixture in portions at 0 °C. The resulting solution was stirred for 2 h at RT. The reaction was then stopped with the addition of 300 ml of ice water. The resulting solution was extracted with 3x300 ml of EtOAc; the combined organic phase was dried over Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:30). This resulted in 7.6 g (55%) of the title compound as a yellow oil. MS-ESI: 322/324 (M+1).

[002113] Steps 5 to 9 used the same procedures to convert compound 34 to Intermediate 3 shown in the Scheme

11 to provide Intermediate 4 from compound 43. MS-ESI: 494 (M+1). Scheme 13A: Intermediate 5

TBS N NH2

S S HOO

N N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide Step 1: Methyl 2-mercaptothiazole-5-carboxylate

[002114] In a 2 L round bottom flask, methyl 2-bromothiazole-5-carboxylate (100 g, 450 mmol) and EtOH (1.0 L) were placed. To the stirred solution, sodium hydrogen sulfide (50 g, 890 mmol) was added in portions with stirring. The resulting solution was stirred for 2 h at 80°C and then cooled to 0°C with a water/ice bath. The pH of the solution was adjusted to 3 with hydrogen chloride (1M). Solids were collected by filtration. This resulted in 63.2 g (80%) of the title compound as a pale yellow solid. MS-ESI: 176.0 (M+1). Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

[002115] In a 1 L round bottom flask, methyl 2-mercaptothiazole-5-carboxylate (30 g, 170 mmol) and acetic acid (300 ml) were placed. This was followed by the addition of sodium hypochlorite (300 ml, 8.0% to 10% by weight) in portions at 0°C. The resulting solution was stirred for 2 h at RT and then diluted with 500 ml of water. The solution was extracted with 3x300 ml of DCM, and the combined organic layers were washed with 2x300 ml of brine and dried over anhydrous Na2SO4. The crude product as a yellow solution in DCM was used in the next step. Step 3: Methyl 2-sulfamoylthiazole-5-carboxylate

[002116] Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate was placed in a 2 L round bottom flask as a crude solution in DCM (900 ml). To the solution, NH3 (g) was introduced below 0 °C for 20 minutes. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtO-Ac/PE (1:5 to 1:3). This resulted in 23 g (75%, 2 steps) of the title compound as a white solid. MS-ESI: 223.0 (M+1). Step 4: 5-(2-hydroxypropan-2-yl)thiazol-2-sulfonamide

[002117] In a 500 ml round bottom flask purged with and maintained under nitrogen, a solution of methyl 2-sulfamoylthiazole-5-carboxylate (15 g, 67.5 mmol) in THF (150 ml) was placed. This was followed by the addition of MeMgBr/THF (3M, 90 ml) dropwise with stirring at 0°C. The resulting solution was stirred for 14 h at RT and then quenched by the addition of 100 ml of NH4Cl (sat.). The resulting solution was extracted with 3x150 ml of DCM, and the organic layers were combined and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:3). This resulted in 11.5 g (78%) of the title compound as a white solid. MS-ESI: 223.0 (M+1).

[002118] Steps 5 through 6 used a similar procedure to convert compound 19 to Intermediate 1 shown in Scheme 8A to provide Intermediate 5 from compound 53. MS-ESI: 336.1 (M+1 ).

Scheme 13B: Intermediate 5

TBS N NH2

S S HOO

N N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide Step 1: Methyl 2-mercaptothiazole-5-carboxylate

[002119] In a 2 L round bottom flask, methyl 2-bromothiazole-5-carboxylate (100 g, 450 mmol) and EtOH (1.0 L) were placed. To the stirred solution, sodium hydrogen sulfide (50 g, 890 mmol) was added in portions with stirring. The resulting solution was stirred for 2 h at 80°C and then cooled to 0°C with a water/ice bath. The pH value of the solution was adjusted to 3 with hydrogen chloride (1M). The solids were collected by filtration. This resulted in 63.2 g (80%) of the title compound as a pale yellow solid. MS-ESI: 176.0 (M+1). Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

[002120] In a 1 L round bottom flask, methyl 2-mercaptothiazole-5-carboxylate (30 g, 170 mmol) and acetic acid (300 ml) were placed. This was followed by the addition of sodium hypochlorite (300 ml, 8.0% to 10% by weight) in portions at 0°C. The resulting solution was stirred for 2 h at RT and then diluted with 500 ml of water. The solution

The mixture was extracted with 3x300 ml of DCM acetate. The combined organic layers were washed with 2x300 ml of brine and dried over anhydrous Na2SO4. The crude product as a yellow solution in DCM was used in the next step. Step 3: Methyl 2-sulfamoylthiazole-5-carboxylate

[002121] Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate was placed in a 2 L round bottom flask as a crude solution in DCM (900 ml). To the solution, NH3 (g) was introduced below 0 °C for 20 minutes. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtO-Ac/PE (1:5 to 1:3). This resulted in 23 g (75%, 2 steps) of the title compound as a white solid. MS-ESI: 223.0 (M+1). Step 4: 5-(2-hydroxypropan-2-yl)thiazol-2-sulfonamide

[002122] In a 500 ml round bottom flask purged with and maintained under nitrogen, a solution of methyl 2-sulfamoylthiazole-5-carboxylate (15 g, 67.5 mmol) in THF (150 ml) was placed. This was followed by the addition of MeMgBr/THF (3M, 90 ml) dropwise with stirring at 0°C. The resulting solution was stirred for 14 h at RT and then quenched by the addition of 100 ml of NH4Cl (sat.). The resulting solution was extracted with 3x150 ml of DCM acetate. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:3). This resulted in 11.5 g (78%) of the title compound as a white solid. MS-ESI: 223.0 (M+1). Step 5: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonamide

[002123] A solution of 5-(2-hydroxypropan-2-yl)thiazol-2-sulfonamide (5.0 g, 22 .5 mmol) in THF (100 ml). Then, to the above, NaH (60% by weight of dis-

oil perfusion, 1.8 g, 45.0 mmol) in portions in an ice/water bath. After stirring for 20 minutes in a water/ice bath, a solution of TBSCl (4.1 g, 27.2 mmol) in THF (10 ml) was added dropwise with stirring at 0 °C. The resulting solution was stirred for 4 h at RT. The reaction was quenched with saturated NH4Cl (100 ml). The resulting solution was extracted with 3 x 100 ml of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude solid was washed with EtO-Ac/hexane (1:5) (2x100ml). This resulted in 6.81 g (90%) of the title compound as a yellow solid. MS-ESI: 337.1 (M+1), 335.1 (M-1) in positive and negative ion mode, respectively. Step 6: N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide

[002124] In a 100 ml 3-necked round bottom flask purged with and maintained under nitrogen, a solution of PPh3Cl2 (3.0 g, 9.0 mmol) in CHCl3 (100 ml) was placed. This was followed by the addition of DIEA (1.54 g, 11.9 mmol) drip with stirring at RT. The resulting solution was stirred for 10 min at RT. This was followed by the addition of a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonamide (2.0 g, 5.9 mmol) in CHCl 3 (30 mL) by dripping with stirring in an ice/water bath. The resulting solution was stirred for 30 min in an ice/water bath. To the previous one, NH3 (g) was introduced below 0 °C for 15 minutes. The resulting solution was stirred for 20 minutes at RT. The solids were removed by filtration, and the filtrate was concentrated, and the residue was dissolved in 300 ml of EtOAc. The solution was washed with brine (2x100ml), dried over Na2SO4 and concentrated in vacuo. The crude solid was washed with CHCl 3 (100 ml). Then, the filtrate was concentrated in vacuo, and the residue was eluted from silica gel with EtOAc/PE (1:10 to 1:3). The original washed solid and the solid from the silica gel purification were combined. This resulted in 1.2 g (60%) of the title compound as a white solid. MS-ESI: 336.1 (M+1). 1

[002125] H-NMR (300 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.12 (s, 2H), 5.78 (s, 1H), 1.51 (s, 6H) , 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H). Table 2. The Intermediates in the Table below were prepared using similar procedures to convert compound 49 to Intermediate 5 shown in Scheme 13B from suitable starting materials. Intermedi- Exa Mass- Structure IUPAC Name No. ta [M+H]+ N'-(tert-butyldimethylsilyl)- Interme-4-(2-hydroxypropan-2-yl)-350 daily 6 5-methylthiazol-2-sulfonimidamide Scheme 14: Intermediate 7

S O S NH2

N N

HO TBS N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide Step 1: (2-Bromothiazol-4-yl)methanol

[002126] In a 500 ml round bottom flask, a solution of ethyl 2-bromothiazole-4-carboxylate (14 g, 59.3 mmol) in EtOH (200 ml) was placed. This was followed by the addition of NaBH4 (2.3 g, 60.5 mmol) in portions at 0 °C. The resulting solution was stirred for 3 h at RT and then quenched by the addition of 100 ml of water. The resulting solution was extracted with 2x200 ml of DCM acetate. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. This resulted in 10.0 g (87%) of the title compound as a colorless oil. MS-ESI: 195.9/193.9 (M+1). Step 2: 2-Bromothiazole-4-carbaldehyde

[002127] In a 250 ml round bottom flask, a solution of (2-bromothiazol-4-yl)methanol (10.0 g, 51.5 mmol) in DCM (100 ml) was placed. To the solution, Dess-Martin reagent (24.0 g, 56.6 mmol) was added. The resulting solution was stirred for 2 h at RT and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:50 to 1:20). This resulted in 8.0 g (81%) of the title compound as a yellow oil. MS-ESI: 193.9/191.9 (M+1). Step 3: 1-(2-Bromothiazol-4-yl)ethanol

[002128] A solution of 2-bromothiazole-4-carbaldehyde (8.0 g, 41.7 mmol) in THF (100 ml ). This was followed by the addition of MeMgBr (3M in THF, 15 ml) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at RT and then quenched by the addition of 100 ml of NH4Cl (sat.). The resulting solution was extracted with 3x100 ml of DCM, and the combined organic layers were concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:10 to 1:5). This resulted in 6.0 g (69%) of the title compound as a brown oil. MS-ESI: 209.9/207.9 (M+1).

Step 4: 2-Bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole

[002129] In a 250 ml round bottom flask, a solution of 1-(2-bromothiazol-4-yl)ethanol (6.0 g, 28.8 mmol) and 1H-imidazole (4.0 g , 58.8 mmol) in DMF (50 ml). To the solution, TBDPSCl (8.7 g, 31.6 mmol) was added. The resulting solution was stirred for 12 h at RT and then diluted with 100 ml of water. The resulting solution was extracted with 3x100 ml of DCM, and the combined organic layers were concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:100 to 1:50). This resulted in 10.0 g (78%) of the title compound as a pale yellow oil. MS-ESI: 448.1/446.1 (M+1). Step 5: 4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazol-2-sulfonyl chloride

[002130] In a 250 ml 3-necked round bottom flask, purged with and maintained under nitrogen, a solution of 2-bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (10.0 g, 22.4 mmol) in THF (100 ml). This was followed by the addition of n-BuLi (2.5M in THF, 11 ml) dropwise with stirring at -78°C. The resulting solution was stirred for 30 min at -78 °C. To the former, SO2 gas was introduced. The reaction was warmed to RT and stirred for 30 min and then concentrated under vacuum. The residue was dissolved in DCM (100 ml), and then NCS (3.6 g, 26.9 mmol) was added. The resulting solution was stirred for 30 min at RT and then concentrated in vacuo. This resulted in 8.0 g (crude product, 77%) of the title compound as a white solid. The crude product was used in the next step. Step 6: N-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazol-2-sulfonamide

[002131] In a 100 ml round bottom flask purged with and maintained under nitrogen, a solution of 4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonyl chloride (8.0 g, 17 .2 mmol) in DCM

(50 ml). To the solution, TEA (3.5 g, 34.6 mmol) and 2-methylpropan-2-amine (1.9 g, 26.0 mmol) were added. The resulting solution was stirred for 2 h at RT and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:15 to 1:5). This resulted in 8.0 g (71%, 2 steps) of the title compound as a brown oil. MS-ESI: 503.2 (M+1). Step 7: N-tert-butyl-4-(1-hydroxyethyl)thiazol-2-sulfonamide

[002132] In a 250 ml round bottom flask, a solution of N-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazol-2-sulfonamide (8.0 g, 15.9 mmol) in THF (100 ml). To the solution, TBAF (9.6 g, 293 mmol) was added. The resulting solution was stirred for 2 h at RT and then diluted with 100 ml of water. The resulting solution was extracted with 3x100 ml of DCM, and the combined organic layers were concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:10 to 1:3). This resulted in 4.0 g (95%) of the title compound as a pale yellow oil. MS-ESI: 265.1 (M+1). Step 8: 4-Acetyl-N-tert-butylthiazole-2-sulfonamide

[002133] In a 100 ml round bottom flask was placed a solution of N-tert-butyl-4-(1-hydroxyethyl)thiazole-2-sulfonamide (4.0 g, 15.1 mmol) in DCM ( 50 ml). To the solution, Dess-Martin reagent (7.1 g, 16.6 mmol) was added. The resulting solution was stirred for 2 h at RT and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:10 to 1:3). This resulted in 3.5 g (88%) of the title compound as a pale yellow oil. MS-ESI: 363.0 (M+1). Step 9: 4-Acetylthiazole-2-sulfonamide

[002134] In a 100 ml round bottom flask, a solution of 4-acetyl-N-tert-butylthiazole-2-sulfonamide (3.5 g, 13.3 mmol) in DCM (5 ml) was placed. To the solution, TFA (20 ml) was added. The solution

The resulting mixture was stirred for 14 h at 40 °C and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:10 to 1:3). This resulted in 2.5 g (91%) of the title compound as a gray solid. MS-ESI: 207.0 (M+1).

[002135] Steps 10 to 12 used similar procedures to convert compound 23 to Intermediate 1 shown in Scheme 8B to provide Intermediate 7 from compound 64. MS-ESI: 336.1 (M+1). Scheme 15: Intermediate 8 N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-4-sulfonimidamide Step 1: 2-(4-(benzylthio)thiazol-2-yl)propan-2 -hello

[002136] A solution of 2-(4-bromo-1,3-thiazol-2-yl)propan-2-ol (2 .0 g, 9.0 mmol) in DME (50 ml). This was followed by the addition of phenylmethanethiol (11.2 g, 90.0 mmol). To the same were added Na2CO3 (1.91 g, 18.0 mmol) and Xphos Pd G2

(2.4 g, 2.7 mmol). The resulting solution was stirred overnight at 80°C. The resulting mixture was diluted with 150 ml of H2O. The resulting solution was extracted with 2x300 ml of EtOAc, dried over anhydrous sodium sulfate and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 800 mg (33%) of the title compound as a white solid. MS-ESI: 226.1 (M+1). Step 2: 2-(2-hydroxypropan-2-yl)thiazol-4-sulfonyl chloride

[002137] In a 100 ml round bottom flask, a solution of 2-(4-(benzylthio)thiazol-2-yl)propan-2-ol (750 mg, 2.83 mmol) in MeCN (20 ml). To the solution, AcOH (0.75 ml) and H 2 O (0.50 ml) were added. This was followed by the addition of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.67 g, 8.48 mmol) at 0 °C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The resulting mixture was diluted with 20 ml of H2O. The resulting solution was extracted with 3x75 ml of DCM and dried over anhydrous sodium sulfate and concentrated. This resulted in 550 mg (80.5%) of the title compound as a crude solid. MS-ESI: 242 (M+1). Step 3: 2-(2-hydroxypropan-2-yl)thiazol-4-sulfonamide

[002138] In a 100 ml round bottom flask was placed a solution of 2-(2-hydroxypropan-2-yl)thiazol-4-sulfonyl chloride (550 mg, 2.28 mmol) in DCM (30 ml ). To the above NH3 (g) was introduced for 10 min at 0°C. The resulting solution was stirred for 20 min at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 450 mg (89%) of the title compound as a yellow solid. MS-ESI: 223 (M+1).

[002139] Steps 4 to 5 used similar procedures to convert compound 24 to Intermediate 1 shown in Scheme 8B to convert Intermediate 8 from compound 70. MS-ESI: 336 (M+1).

Scheme 16: Intermediate 9

the NH2

S S N TBS

HO N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide Step 1: Methyl 5-(chlorosulfonyl)-2-methylthiophene-3-carboxylate

[002140] In a 250 ml round bottom flask was placed methyl 2-methylthiophene-3-carboxylate (5.0 g, 32 mmol), CHCl 3 (70 ml). This was followed by the addition of ClSO2OH (5.6 g, 48 mmol) dropwise with stirring. Thereto, PCl5 (13 g, 64 mmol) was added with stirring. The resulting solution was stirred for 2 h at 60 °C in an oil bath. The reaction was then quenched by the addition of 150 ml of water/ice. The resulting solution was extracted with 3x80 ml of DCM and dried over anhydrous sodium sulfate and concentrated. This resulted in 5.2 g (64%) of the title compound as a yellow solid.

[002141] Steps 2 through 5 used similar procedures to convert compound 51 to intermediate 5 shown in Scheme 13B to the

[002142] Intermediate 9 from compound 73. MS-ESI: 349 (M+1).

Table 3. The Intermediate in the following Table was prepared using a similar procedure as shown in Scheme 16 above to convert compound 72 to Intermediate 9 from suitable materials. Intermediate- Exact Mass Structure IUPAC Name No. [M+H]+ TBS N'-(tert-butyldimethylsilyl)-

N Intermediate- 5-(2-hydroxypropan-2-S NH2 335.1rio 10 S Oyl)thiophene-2-

HO sulfonimidamide TBS N'-(tert-butyldimethylsilyl)-

N Intermediate- NH2 4-(2-hydroxypropan-2-S 335.1rio 11 HO Oyl)thiophene-2-

S sulfonimidamide N'-(tert-butyldimethylsilyl)-

F

3-Fluoro-5-(2-Intermediate-S NH2 hydroxypropan-2-353.1rio 12 S

No HO

TBS yl)thiophene-2-sulfonimidamide Scheme 17: Intermediate 13

N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonimidamide Step 1: 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate of ethyl

[002143] In a 250 ml round bottom flask, purged and maintained with an inert atmosphere of oxygen, was placed ethyl 3-nitro-1H-pyrazole-5-carboxylate (5 g, 27 mmol) in tetrahydrofuran (150 ml). To the stirred solution, phenylboronic acid (6.6 g, 54 mmol), Cu(OAc) 2 (7.38 g, 41 mmol) and pyridine (8.54 g, 108 mmol) were added. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 3.1 g (44%) of the title compound as an off-white solid. MS-ESI: 262 (M+1). Step 2: Ethyl 3-amino-1-phenyl-1H-pyrazole-5-carboxylate

[002144] In a 100 ml round bottom flask, ethyl 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate (3.92 g, 15 mmol) and methanol (50 ml) were placed. To the stirred solution, Pd/C (10 wt% wet, 400 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred overnight at RT. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. This resulted in 2.8 g (81%) of the title compound as a pale yellow solid. MS-ESI: 232 (M+1). Step 3: Ethyl 3-(chlorosulfonyl)-1-phenyl-1H-pyrazole-5-carboxylate

[002145] In a 100 ml round bottom flask was placed ethyl 3-amino-1-phenyl-1H-pyrazole-5-carboxylate (1.8 g, 7.78 mmol) in HCl (6 M, 15 ml). This was followed by the addition of a solution of Na-NO2 (646 mg, 9.36 mmol) in water (2 ml) dropwise with stirring at -10 °C. The resulting solution was stirred for 30 min at -10 °C. The above mixture was added to a saturated solution of SO 2 in AcOH (20 ml) dropwise with stirring at 0°C. Then, to the above, CuCl2 (1.05 g, 7.81 mmol) was added. The resulting solution was stirred for 1 h at RT. The reaction was then stopped with the addition of 30 ml of water. The resulting solution was extracted with 3x30 ml of DCM acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 2.2 g (90%) of the title compound as a pale yellow solid. Step 4: Ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate

[002146] In a 100 ml round bottom flask, a solution of ethyl 3-(chlorosulfonyl)-1-phenyl-1H-pyrazole-5-carboxylate (2.2 g, 6.99 mmol) in DCM was placed (10 ml). Then, to the previous one, NH3 gas was bubbled at 0 °C for 10 min. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated in vacuo. The residue was applied to silica gel with EtOAc/PE (1:1). This resulted in 1.07 g (52%) of the title compound as a pale yellow solid. MS-ESI: 296 (M+1). Step 5: 5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonamide

[002147] A solution of ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate ( 1.65 g, 5.59 mmol) in tetrahydrofuran (30 ml). This was followed by the addition of MeMgBr (3M in THF, 18.6 ml) dropwise with stirring at 0°C. The resulting solution was stirred by droplet at RT. The reaction was then quenched by the addition of 30 ml of NH4Cl (sat.). The resulting solution was extracted with 3x30 ml of DCM, and the organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (2:1). This resulted in 1.35 g (86%) of the title compound as a yellow solid. MS-ESI: 282 (M+1).

Step 6: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonamide

[002148] Into a 100 ml round bottom flask was placed 5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonamide (500 mg, 1.78 mmol) in tetra- hydrofuran (10 ml). This was followed by the addition of sodium hydride (60% by weight of oil dispersion, 143 mg, 3.58 mmol) in portions at 0°C. Then, to the above, TBSCl (538 mg, 3.57 mmol) was added. The resulting solution was stirred for 2 h at RT. The reaction was then stopped with the addition of 10 ml of water. The resulting solution was extracted with 3x10 ml of DCM acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 660 mg (94%) of the title compound as a pale yellow solid. MS-ESI: 396 (M+1). Step 7: N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonimidamide

[002149] In a 100 ml 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, a solution of PPh3Cl2 (1.67 g, 5.01 mmol) in chloroform (30 ml) was placed. . This was followed by the addition of DIEA (1.29 g, 9.98 mmol) drip with stirring at RT. The resulting solution was stirred for 10 min at RT, and the reaction system was cooled to 0 °C. Thereto, a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonamide (660 mg, 1.67 mmol) was added. in chloroform (3 ml) dropwise with stirring at 0°C. The resulting solution was stirred for 30 min at 0 °C. To the mixture, NH3 gas was bubbled for 15 min at 0 °C. The resulting solution was stirred for 2 h at RT, after which it was diluted with 30 ml of water. The resulting solution was extracted with 3x30 ml of DCM acetate. The organic layers were combined, dried with anhydrous sodium sulfate, and

vacuum centered. The residue was eluted from silica gel with EtO-Ac/PE (1:1). This resulted in 530 mg (81%) of the title compound as a pale yellow solid. MS-ESI: 395 (M+1). Scheme 18: Intermediate 14 N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-sulfonimidamide Step 1: 1-methyl-3-nitro-1H- ethyl pyrazole-5-carboxylate

[002150] In a 100 ml 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, the solution of ethyl 3-nitro-1H-pyrazole-5-carboxylate (1.0 g , 5.41 mmol) in DMF (20 ml). This was followed by the addition of K2CO3 (1.49 g, 10.8 mmol) in portions at 0 °C. Then, to the above, CH3I (922 mg, 6.49 mmol) was added dropwise at 0 °C in an ice bath. The resulting solution was stirred for 16 h at RT. The reaction was then stopped with the addition of 10 ml of water. The resulting solution was extracted with 3x10 ml of DCM acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 807 mg (75%) of the title compound as a light yellow solid. MS-ESI: 200 (M+1).

[002151] Steps 2 to 7 used similar procedures to convert compound 78 to intermediate 13 shown in Scheme 17 to provide intermediate 14 from compound 84. MS-ESI: 333 (M+1). Scheme 19: Intermediate 15

TBS

N Y NH2

N N

N'-(tert-butyldimethylsilyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide Step 1: 1-Isopropyl-3-nitro-1H-pyrazole

[002152] In a 250 ml round bottom flask, a solution of 3-nitro-1H-pyrazole (10 g, 88.4 mmol) in DMF (100 ml) was placed. This was followed by the addition of NaH (60% by weight, 3.9 g, 97.5 mmol) in portions at 0 °C. The resulting solution was stirred for 0.5 h at 0 °C. This was followed by the addition of 2-bromopropane (14.1 g, 115 mmol) dropwise with stirring at 0 °C in 10 min. The resulting solution was stirred for 16 h at RT and then quenched by the addition of 100 ml of water. The resulting solution was extracted with 3x100 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was eluted from silica gel with an EtOAc/PE gradient (1:5 to 1:3). This resulted in 11.8 g (86%) of the title compound as a yellow oil. MS-ESI: 156.1 (M+1).

[002153] Steps 2 to 6 used similar procedures to convert compound 78 to intermediate 13 shown in Scheme 17 to provide intermediate 15 from compound 91. MS-ESI: 333 (M+1). Scheme 20: Intermediate 16 N'-(tert-butyldimethylsilyl)-1-(difluoromethyl)-1H-pyrazol-3-sulfonimidamide Step 1: 1-(Difluoromethyl)-3-nitro-1H-pyrazole

[002154] In a 250 ml round bottom flask, a solution of 3-nitro-1H-pyrazole (5 g, 44 mmol) in DMF (40 ml) was placed. To the stirred solution, Cs2CO3 (14.4 g, 44 mmol) and F2ClCCOONa (13.4 g, 88 mmol) were added. The resulting solution was stirred for 30 min at 120 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x100 ml of EtO-Ac. The resulting mixture was washed with 3x100 ml of brine. The mis-

The mixture was dried over anhydrous sodium sulfate. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 4.3 g (59.6%) of 1-(difluoromethyl)-3-nitro-1H-pyrazole as a yellow oil.

[002155] Steps 2 to 7 used similar procedures to convert compound 78 to intermediate 13 shown in Scheme 17 to provide intermediate 16 from compound 96. MS-ESI: 311 (M+1). Scheme 21: Intermediate 17 NH2

HO S N

N O TBS N'-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-sulfonimidamide Step 1: Methyl 5-amino-6-methylpicolinate

[002156] In a 50 ml seal tube, methyl 6-bromo-2-methylpyridin-3-amine (500 mg, 2.67 mmol) in MeOH (15 ml) was placed. To the stirred solution, Pd(OAc) 2 (120 mg, 0.53 mmol), dppf (444 mg, 0.80 mmol) and TEA (809 mg, 8.01 mmol) were added with stirring. The sealing tube was evacuated and washed three times with CO. The resulting solution was stirred for 5 h at 100 °C under 10 atm of CO. Then, the solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 351 mg (79.2%) of the title compound as a pale yellow solid. MS-ESI: 167 (M+1).

[002157] Steps 2 through 6 used similar procedures to con-

pouring compound 79 into Intermediate 13 shown in Scheme 17 to provide Intermediate 17 from compound 103''. MS-ESI: 344 (M+1). Table 4. The Intermediates in the Table below were prepared using similar procedures to convert compound 102'' to Intermediate 17 shown in Scheme 21 from suitable starting materials. Intermediate Exa Mass Structure IUPAC Name No. ta[M+H]+ N'-(tert-butyldimethylsilyl)-6-(2-Intermedihydroxypropan-2-330aryl)pyridine-3-sulfonimidamide Scheme 22: Intermediate 19

No THE

S NH2

No

TBS N'-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)benzenesulfonimidamide Step 1: 4-Nitrobenzoyl chloride

[002158] In a 500 ml round bottom flask was placed 4-nitrobenzoic acid (20 g, 120 mmol) in DCM (200 ml) and DMF (0.2 ml). This was followed by the addition of oxalyl chloride (15 ml, 135 mmol) dropwise with stirring at 0 °C. The resulting solution was stirred for 4 h at RT and then concentrated in vacuo. This resulted in 22 g of the crude title compound as a yellow oil. The crude product was used in the next step. Step 2: N,N-dimethyl-4-nitrobenzamide

[002159] In a 500 ml round bottom flask, dimethylamine hydrochloride (9.8 g, 120 mmol) was placed in DCM (200 ml) and TEA (41.5 ml, 300 mmol). This was followed by the addition of 4-nitrobenzoyl chloride (22 g, crude product) dropwise with stirring at 0 °C. The resulting solution was stirred for 6 h at RT and then concentrated in vacuo. The resulting mixture was washed with 2x50 ml of water. The solids were collected by filtration. This resulted in 16 g (69%, 2 steps) of the title compound as a white solid. MS-ESI: 195.1 (M+1). Step 3: 4-Amino-N,N-dimethylbenzamide

[002160] In a 250 ml round bottom flask was placed N,N-dimethyl-4-nitrobenzamide (16 g, 82.4 mmol) in MeOH (100 ml), to the above solution was added Pd/C ( wet, 10% by weight, 1.0 g). The flask was evacuated and washed three times with hydrogen. The resulting solution was stirred for 12 h at RT under a hydrogen atmosphere. The Pd/C catalysts were removed by filtration, and the filtrate was concentrated in vacuo. This resulted in 13 g (96%) of the title compound as a white solid. MS-ESI: 165.1 (M+1). Step 4: 4-(Dimethylcarbamoyl)benzene-1-sulfonyl chloride

[002161] In a 50 ml round bottom flask was placed 4-amino-N,N-dimethylbenzamide (3.0 g, 18.3 mmol) in HCl (6 M, 12 ml). This was followed by the addition of the NaNO2 solution (1.5 g, 21.7 mmol)

in water (3 ml) by drip with stirring at 0°C. The resulting solution was stirred for 30 min at 0°C. The above mixture was added to a saturated solution of SO 2 in AcOH (100 ml) dropwise with stirring at 0°C. To the above, CuCl 2 (4.8 g, 35.7 mmol) was added. The resulting solution was stirred for 2 h at RT and then quenched by the addition of 100 ml of water. The resulting solution was extracted with 2x100 ml of DCM acetate. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. This resulted in 5 g of the crude title compound as a yellow oil. The crude product was used in the next step. Step 5: N,N-dimethyl-4-sulfamoylbenzamide

[002162] In a 250 ml round bottom flask was placed 4-(dimethylcarbamoyl)benzenyl-1-sulfonyl chloride (5 g, 20.2 mmol) in DCM (20 ml). To the above solution, a saturated solution of ammonia in DCM (80 ml) was added. The resulting solution was stirred for 2 h at RT and then concentrated in vacuo. The resulting mixture was washed with 3x100 ml of EtOAc. Solids were removed by filtration. The resulting filtrate was concentrated in vacuo. This resulted in 3.1 g (67%) of the title compound as a white solid. MS-ESI: 229.1 (M+1). Step 6: 4-((Dimethylamino)methyl)benzenesulfonamide

[002163] In a 100 ml round bottom flask purged with and maintained under nitrogen, a solution of N,N-dimethyl-4-sulfamoylbenzamide (1.8 g, 7.9 mmol) in THF (50 ml) was placed. . This was followed by the addition of 9-BBN (5.8 g, 47.5 mmol) in portions at 0 °C. The resulting solution was stirred for 12 h at 70°C and then quenched by the addition of 20 ml of water/ice. The resulting solution was extracted with 3x100 ml of EtOAc, and the organic layers were combined. The resulting mixture was washed with 200 ml of water and then the organic layer was concentrated in vacuo. The residue was Pd/C, a silica gel with DCM/MeOH (20:1 to 15:1). This resulted in 1.0 g (59%) of the title compound as a white solid. MS-ESI: 215.1 (M+1).

[002164] Steps 7 to 8 used similar procedures to convert compound 82 to intermediate 13 shown in Scheme 17 to provide Intermediate 19 from compound 114''. MS-ESI: 328 (M+1). Table 4. The Intermediates in the Table below were prepared using similar procedures to convert compound 108'' to Intermediate 19 shown in Scheme 22 from suitable starting materials. Interme- Structure Name IUPAC Exasurable Mass No. ta[M+H]+

F N'-(tert-butyldimethylsilyl)-4-Interme-N

TBS ((dimethylamino)methyl)-2-N S NH 346.2 daily 20 2 fluorobenzenesulfonym-

The damida Scheme 23: Intermediate 21

N'-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-N-methylbenzenesulfonimidamide

[002165] Steps 1 to 7 used similar procedures to convert compound 108'' to compound 115'' shown in Scheme 22 to provide compound 123'' from compound 116''. MS-ESI: 329 (M+1). Step 9: N'-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-N-methylbenzenesulfonimidamide

[002166] In a 500 ml 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, a solution of PPh3Cl2 (13 g, 39 mmol) in chloroform (150 ml) was placed. This was followed by the addition of DIEA (10 g, 78 mmol) drip with stirring at RT. The resulting solution was stirred for 10 min at RT, and the reaction system was cooled to 0 °C. Thereto, a solution of N-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)benzenesulfonamide (3.2 g, 9.76 mmol) in chloroform (30 ml) was added dropwise with stirring at 0°C. °C The resulting solution was stirred for 30 min at 0 °C. To the mixture, CH3NH2 (14.6 ml, 29.3 mmol, 2M) was added for 15 min at 0 °C. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 100 ml of water. The resulting solution was extracted with 3x200 ml of DCM acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (36/64). This resulted in 1.43 g (43%) of the title compound as a yellow solid. MS-ESI: 342 (M+1).

Scheme 24: Intermediate 22 and Intermediate 22A (blend) N'-(tert-butyldimethylsilyl)-4-(1-hydroxycyclopropyl)thiophene-2-sulfonimidamide and N'-(tert-butyldimethylsilyl)-4-propionylthiophene-2-sulfonimidamide

[002167] Steps 1 to 2 used similar procedures to convert compound 72 to compound 74 shown in Scheme 16 to provide compound 126'' from compound 124''. MS-ESI: 221 (M+1). Step 3: Mixture of 4-(1-hydroxycyclopropyl)thiophene-2-sulfonamide and 4-propionylthiophene-2-sulfonamide

[002168] To a solution of methyl 5-sulfamoylthiophene-3-carboxylate (5.0 g, 22.6 mmol) in THF (100 mL) under nitrogen was added Ti(Oi-Pr) 4 (1.28 g , 4.52 mmol) by dripping at 0°C. This was followed by the addition of EtMgBr (3M in Et2O, 45 ml, 135 mmol) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched with 50 ml of saturated NH4Cl (aq.). The resulting solution was extracted with 5x100 ml of EtOAc. The combined organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (25:1). This resulted in 1.66 g (33.5%) of the title compounds (~1:1 mixture) as a pale yellow solid. MS-ESI: both 220 (M+1).

[002169] Steps 4 to 5 used similar procedures to convert compound 82 to Intermediate 13 shown in Scheme 17 to provide the (~1:1) mixture of Intermediate 22 and Intermediate 22A from the mixture of compound 127'' and 127A''. MS-ESI: both 333 (M+1).

[002170] Steps 4 to 5 used similar procedures to convert compound 82 to intermediate 13 shown in Scheme 17 to provide intermediate 22 from compound 127''. MS-ESI: 333 (M+1). Scheme 25: Intermediate 23 N'-(tert-butyldimethylsilyl)-4-isopropylthiophene-2-sulfonimidamide

Step 1: 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide

[002171] In a 250 ml 3-necked round bottom flask, purged with and maintained under nitrogen, was placed a solution of methyl 5-sulfamoylthiophene-3-carboxylate (4.42 g, 20 mmol) in THF (200 ml ). This was followed by the addition of MeMgBr (3M in THF, 40 ml) dropwise with stirring at 0°C. The resulting solution was stirred for 16 h at RT and then quenched by the addition of 100 ml of NH4Cl (sat.). The resulting solution was extracted with 3x100 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was applied to a silica gel and eluted with an EtOAc/PE gradient (1:3 to 1:1). This resulted in 2.21 g (50%) of the title compound as a pale yellow solid. MS-ESI: 220.2 (M-1). Step 2: 4-Isopropylthiophene-2-sulfonamide

[002172] In a 250 ml round bottom flask, a solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (1.5 g, 6.79 mmol) in DCM (20 ml ). To the stirred solution, TFA (3.9 g, 34 mmol) and Et3SiH (2.32 g, 20 mmol) were added. The resulting solution was stirred overnight at RT. The mixture was concentrated in vacuo. The residue was eluted from silica gel with an EtO-Ac/PE gradient (1:5 to 1:3). This resulted in 1.1 g (79%) of the title compound as a pale yellow solid. MS-ESI: 206 (M+1).

[002173] Steps 3 to 5 used similar procedures to convert compound 82 to intermediate 13 shown in Scheme 17 to provide intermediate 23 from compound 130''. MS-ESI: 319 (M+1).

Scheme 26: Intermediate 24 N'-(tert-butyldimethylsilyl)-1-isopropyl-1H-pyrazol-4-sulfonimidamide

[002174] Steps 1 to 4 used similar procedures to convert compound 98 to intermediate 16 shown in Scheme 20 to provide intermediate 24 from compound 133''. MS-ESI: 303 (M+1). Scheme 27: Intermediate 25

N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)-4-(methoxymethyl)thiazol-5-sulfonimidamide Step 1: 2-Bromo-4-(methoxymethyl)thiazole

[002175] In a 500 ml round bottom flask, a solution of (2-bromothiazol-4-yl)methanol (10 g, 51.8 mmol) in THF (200 ml) was placed. To a stirred solution, NaH (60% by weight of oil dispersion, 4.15 g, 104 mmol) was added at three times at 0 °C in an ice/ethanol bath. To this reaction solution, MeI (11 g, 77.7 mmol) was added dropwise with stirring at 0 °C in an ice/ethanol bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 ml) at 0°C. The resulting solution was extracted with 3x300 ml of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 8.58 g (80%) of the title compound as a white solid. MS-ESI: 208/210 (M+1).

[002176] Steps 2 to 6 used similar procedures to convert compound 34 to intermediate 3 shown in Scheme 11 to provide intermediate 25 from compound 137''. MS-ESI: 380 (M+1). Scheme 28: Intermediate 26

tert-Butyl (amino(4-((dimethylamino)methyl)phenyl)(oxo)-λ6-sulfanoylidene)carbamate Step 1: 1-(4-Bromophenyl)-N,N-dimethylmethanamine

[002177] To a solution of 1-bromo-4-(bromomethyl)benzene (125 g, 500 mmol) in DCM (2.5 L), was added EtOH/MeNH 2 (268 mL, 33% in EtOH). The resulting mixture was heated at reflux for 6 h. The reaction was then cooled to room temperature and poured into saturated NaHCO3 (1.2 L) before extraction with EtOAc (4x1.0 L). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on silica gel with EtOAc/petroleum ether (1:1). This resulted in 83 g (77%) of the title compound as a yellow solid. MS-ESI: 214/216 (M+1).

[002178] Steps 2 to 7 used similar procedures to convert compound 26 to intermediate 2 shown in Scheme 9 to provide intermediate 26 from compound 143''. MS-ESI: 314 (M+1). Scheme 29: Intermediate 27

N'-(tert-butyldimethylsilyl)-4-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide Step 1: Methyl 3-fluorothiophene-2-carboxylate

[002179] In a 250 ml round bottom flask was placed 3-fluorothiophene-2-carboxylic acid (10 g, 68 mmol) in MeOH (10 ml) and H2SO4 (50 ml). The resulting solution was stirred overnight at 60°C. The reaction was then quenched by the addition of 100 ml of water/ice. The resulting solution was extracted with 2x100 ml of ethyl acetate. The organic layers were combined, dried and concentrated. This resulted in 9.6 g (87.60%) of methyl 3-fluorothiophene-2-carboxylate as a gray solid. MS-ESI: 161 (M+1).

[002180] Step 2 used similar procedures to convert compound 72 to compound 73 shown in Scheme 16 to compound 151'' from compound 150''.

[002181] Steps 3 to 6 used similar procedures to convert compound 51 to intermediate 5 shown in Scheme 13B to Intermediate 27 from compound 151''. MS-ESI: 353 (M+1).

[002182] Schemes for Phenylacetic Acid Intermediates: Schemes 30 to 36 illustrate the preparation of amino pyridine intermediates. Scheme 30: Intermediate 28 3,5-diisopropylpyridin-4-amine

Step 1: 3,5-Di(prop-1-en-2-yl)pyridin-4-amine

[002183] In a 500 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 3,5-dibromopyridin-4-amine (5.0 g, 20 mmol) in dioxane (150 ml) was placed. and water (15 ml). To the stirred solution, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (10 g, 60 mmol), Cs2CO3 (19.6 g, 60 mmol) and Pd(dppf)Cl 2 (1.46 g, 2.0 mmol). The resulting solution was stirred for 15 h at 90 °C in an oil bath. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 3.0 g (87%) of the title compound as a pale yellow oil. MS-ESI: 175 (M+1). Step 2: 3,5-diisopropylpyridin-4-amine

[002184] In a 250 ml round bottom flask was placed 3,5-bis(prop-1-en-2-yl)pyridin-4-amine (3.0 g, 17.2 mmol) in MeOH ( 50 ml) and Pd/C (wet, 10% by weight, 300 mg). The flask was evacuated and washed three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were removed by filtration, the filtrate was concentrated in vacuo. This resulted in 2.8 g (91%) of the title compound as a pale yellow solid. MS-ESI: 178 (M+1). Table 6. The Intermediates in the Table below were prepared using similar procedures to convert compound 155'' to Intermediate 28 shown in Scheme 30 from suitable starting materials. Intermediate- Structure IUPAC Name Exar Mass no. ta[M+H]+ 5-fluoro-2,4-di- Intermediate-isopropylpyridin-3-197ryl 29 amine

2-Fluoro-3,5-di- Intermediate-isopropylpyridin-4-amine 2,4-di-179 Intermediate-isopropylpyridin-3-amine Scheme 31: Intermediate 32 2,3,5,6-Tetramethylpyridin -4-amine Step 1: 3,5-Dibromo-2,6-dimethylpyridin-4-amine

[002185] In a 250 ml round bottom flask was placed 2,6-dimethylpyridin-4-amine (5.0 g, 40.9 mmol) in ACN (100 ml). This was followed by the addition of NBS (14.6 g, 81.9 mmol) in several batches at 0 °C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 10.6 g (93%) of the title compound as a yellow solid. MS-ESI: 279/281/283(M+1). Step 2: 2,3,5,6-Tetramethylpyridin-4-amine

[002186] In a 100 ml round bottom flask, purged and maintained with an inert atmosphere of nitrogen, 3,5-dibromo-2,6-dimethylpyridin-4-amine (2.0 g, 7, 1 mmol) in dioxane (30 ml) and H 2 O (6.0 ml). To the above solution, Cs2CO3 (4.66 g, 14.3 mmol), methylboronic acid (941 mg, 15.7 mmol) and Pd(dppf)Cl2 (523 mg, 0.71 mmol) were added. The resulting solution was stirred for 16 h at 100 °C in an oil bath. Solids were removed by filtration. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 220 mg (20.5%) of the title compound as a red solid. MS-ESI: 151 (M+1). Scheme 32A: Intermediate 33 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine Step 1: 2-Aminocyclopent-1-ene-1-carbonitrile

[002187] In a 500 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, a mixture of adiponitrile (10.8 g, 100 mmol) in toluene (250 ml) was placed. The reaction mixture was heated to 65 °C, and t-BuOK (112 g, 100 mmol) was added to the 65 °C solution in portions. The resulting solution was stirred at 80 °C for 8 h. The reaction mixture was then cooled to RT and quenched by the addition of 200 ml of water/ice. The solids were collected by filtration. The filter cake was washed with water (100 ml) and hexane (200 ml), after which it was dried under an infrared lamp. This resulted in 9.18 g (85.0%) of the title compound as an off-white solid. MS-ESI: 109 (M+1). Step 2: 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

[002188] In a 250 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 2-aminocyclopent-1-ene-1-carbonitrile (5.0 g, 46.2 mmol) in xylene was placed (125 ml). To the above solution, cyclopentanone (7.8 g, 93 mmol) and ZnCl 2 (6.9 g, 51 mmol) were added. The resulting solution was stirred overnight at 140 °C in an oil bath.

The resulting solution was diluted with 150 ml of MeOH, after which a solution of KOH (25 ml, 5.0 M) was dropped into it.

Solids were removed by filtration.

The resulting mixture was concentrated.

The residue was dissolved in 250 ml of EtOAc.

The solids were collected by filtration.

This resulted in 4.2 g (52%) of the title compound as a brown solid.

MS-ESI: 175 (M+1). Table 7. Intermediate 33 and Intermediate 34 in the Table below were separated from the same reaction using similar procedures to convert compound 160'' to Intermediate 33 shown in Scheme 32A from 3-methylcyclopentanone.

Intermediate- Structure Name IUPAC Exar Mass no. ta[M+H]+

2-Methyl-1,2,3,5,6,7-hexa-Intermediate-hydrodicyclopentarium 34 ta[b,e]pyridin-8-amine

1-Methyl-1,2,3,5,6,7-hexa- Intermediate-hydrodicyclopentarium 35 ta[b,e]pyridin-8-amine

Table 8. The Intermediates in the Table below were prepared using similar procedures to convert compound 160'' to Intermediate 33 shown in Scheme 32A from suitable starting materials.

Intermediate- Structure Name IUPAC Exar Mass no. ta[M+H]+

2,3,5,6,7,8-hexahydro-Intermediate-1H-cyclopenta[b]quinolinium 36 9-amine

2,2-Dimethyl-1,2,3,5,6,7- Intermediate-hexadium 37-hydrodicyclopenta[b,e]pyridin-8-amine

3-Ethyl-2-phenyl-6,7-dihydro-Intermediate-5H-cyclopenta[b]pyridin-4-amine

3-Methyl-2-phenyl-6,7-di-Intermediate-5H-cyclopenta[b]pyridin-4-amine

2-phenyl-6,7-dihydro-5H-Intermediate-cyclopenta[b]pyridin-4-amine

2,3-dimethyl-6,7-dihydro-Intermediate-5H-cyclopenta[b]pyridin-4-amine

2-Ethyl-6,7-dihydro-5H-Intermediate-cyclopenta[b]pyridin-4-amine

3,5-Dimethyl-1,2,3,5,6,7- Intermediate-hexadium 43 hydrodicyclopenta[b,e]pyridin-8-amine

2-cyclopropyl-3-methyl-6,7-Intermediate-dihydro-5H-cyclopenta[b]pyridin-4-amine Scheme 32B: Intermediate 33 1,2,3,5,6,7-hex -hydrodicyclopenta[b,e]pyridin-8-amine

[002189] In a 250 ml 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 2-aminocyclopent-1-enecarbonitrile (5.4 g, 50 mmol) in DCE (125 ml). To this solution, cyclopentanone (8.4 g, 100 mmol) was added. Then, BF3.Et2O (46.5% by weight, 14.5 g) was added to this solution at 0 °C in an ice bath. The reaction was heated at 75 °C for 6 h. The reaction cooled to RT, after which it was quenched by the addition of 100 ml of water/ice and extracted with DCM (2x50 ml). The aqueous phase was collected. The pH value was adjusted to 14 with NaOH (6M) until the solid had precipitated. The solids were collected by filtration. The filter cake was washed with water (150 ml) then dried by infrared drying, this resulted in the title compound (7.0 g, 80% yield, light yellow solid). MS-ESI: 175 (M+1).

Table 9. The Intermediates in the Table below were prepared using similar procedures to convert compound 160'' to Intermediate 33 shown in Scheme 32B from suitable starting materials.

Interme- Structure Name IUPAC Daily Exact Mass No. [M+H]+

3-Methyl-1,2,3,5,6,7-Intermehexa-daily 45 hydrodicyclopenta[b,e]pyridin-8-amine

3,3-dimethyl-1,2,3,5,6,7-Intermexa-daily 46 hydrodicyclopenta[b,e]pyridin-8-amine

1',5',6',7'-tetrahydro-2'H-spiro[cyclopropane-Interme-1,3'-daily 201 47 dicyclopenta[b,e]pyridin]-8'-amine

2-cyclopropyl-6,7-di-Intermehydro-5H- 175 daily 48 cyclopenta[b]pyridin-4-amine

2-isopropyl-6,7-dihydro-Interme-5H-cyclopenta[b]pyridin-177 daily 49 4-amine

Scheme 33: Intermediate 50 3-Isopropyl-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 3-Bromo-2-phenyl-6,7-dihydro -5H-cyclopenta[b]pyridin-4-amine

[002190] In a 100 ml round bottom flask was placed 2-phenyl-5H,6H,7H-cyclopenta[b]pyridin-4-amine (1.36 g, 6.47 mmol) in ACN (20 ml ). To the stirred solution, NBS (1.38 g, 7.76 mmol) was added. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 680 mg (36.4%) of the title compound as a yellow solid. MS-ESI: 289/291 (M+1). Step 2: 2-phenyl-3-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002191] In a 100 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 3-bromo-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin- 4-amine (680 mg, 2.35 mmol) in dioxane (15 ml) and H 2 O (3 ml). To the stirred solution, Cs2CO3 (1.53 g, 4.7 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-

dioxaborolane (474 mg, 2.8 mmol) and Pd(dppf)Cl 2 (86 mg, 0.12 mmol). The resulting solution was stirred for 16 h at 100 °C in an oil bath. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 350 mg (59%) of the title compound as a pale yellow solid. MS-ESI: 251 (M+1). Step 3: 3-Isopropyl-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002192] In a 100 ml round bottom flask purged and maintained with an inert atmosphere of H2, 2-phenyl-3-(prop-1-en-2-yl)-6,7-di- hydro-5H-cyclopenta[b]pyridin-4-amine (350 mg, 1.4 mmol) in MeOH (15 ml). To the stirred solution, Pd/C (wet, 10% by weight, 50 mg, 0.47 mmol) was added. The flask was evacuated and washed three times with hydrogen. The resulting solution was stirred for 16 h at 50 °C under an atmosphere of hydrogen. The Pd/C catalysts were removed by filtration, the filtrate was concentrated in vacuo. This resulted in 250 mg (71%) of the title compound as a yellow solid. MS-ESI: 253 (M+1). Table 10. The Intermediates in the following Table were prepared using similar procedures to convert intermediate 40 to Intermediate 50 shown in Scheme 33 from suitable starting materials. Interme- Structure IUPAC Name Daily Exact Mass # [M+H]+ 3-ethyl-2-methyl-6,7-di- Intermehydro-5H- 177 daily 51 cyclopenta[b]pyridin-4-amine 3-isopropyl -2-methyl-6,7-Intermedihydro-5H- daily 52 cyclopenta[b]pyridin-4-amine

Interme- Structure Name IUPAC Exact Mass Daily # [M+H]+ 2-Propyl-6,7-dihydro- Interme-5H-cyclopenta[b]pyridin-177 daily 53 4-amine 2-cyclopropyl-3-ethyl -6,7- Intermediate-dihydro-5H- 54 cyclopenta[b]pyridin-4-amine Scheme 34: Intermediate 55 3-Fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[ b,e]pyridin-8-amine Step 1: N-(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)acetamide

[002193] A solution of 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (35 g, 201 mmol) in Ac2O (805 ml). This was followed by the addition of triethylamine (61 g, 603 mmol) dropwise with stirring at 0°C in 5 min. The resulting solution was stirred overnight at 100 °C in an oil bath. The mis-

resulting mixture was concentrated in vacuo. The pH value of the solution was adjusted to 14 with aqueous KOH (20M). The solids were collected by filtration. This resulted in 31 g (71%) of the title compound as a brown solid. MS-ESI: 217 (M+1). Step 2: 8-acetamido-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide

[002194] A solution of N-(1,2,3,5,6,7-hexahydrodicyclopenta[b,e] pyridin-8-yl)acetamide (31.4 g, 145 mmol) in DCM (250 ml). This was followed by the addition of m-CPBA (75 g, 436 mmol) dropwise with stirring at 0 °C in 5 min. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (24:1). This resulted in 14 g (42%) of the title compound as a white solid. MS-ESI: 233(M+1). Step 3: 8-Acetamido-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl acetate

[002195] In a 250 ml round bottom flask, 8-acetamido-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide (14.9 g, 64 mmol) in Ac2O (80 ml). The resulting solution was stirred for 1 h at 100 °C in an oil bath. The resulting mixture was concentrated. This resulted in 16 g of crude title compound as a crude black solid. MS-ESI: 275 (M+1). Step 4: N-(3-hydroxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)acetamide

[002196] In a 250 ml round bottom flask, a solution of 8-acetamido-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl acetate ( 4.5 g, 16.4 mmol) in ethanol (100 ml), to the above solution, KOH (550 mg, 9.84 mmol) was added with stirring. The resulting solution was stirred overnight at RT.

The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (26:1). This resulted in 2.1 g (55%) of the title compound as a pale yellow solid. MS-ESI: 233 (M+1). Step 5: 8-Amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol

[002197] In a sealed 8 ml tube, a solution of N-(3-hydroxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)acetamide was placed (200mg, 0.86mmol) in HCl (4M, 3ml). The resulting solution was stirred for 40 min at 100 °C. The pH value of the solution was adjusted to 7 with NaOH (1M). The resulting mixture was concentrated. The residue was applied to a silica gel with DCM/MeOH (3:1). This resulted in 80 mg (49%) of the title compound as a yellow solid. MS-ESI: 191 (M+1). Step 6: 3-Fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

[002198] In a sealed 8 ml tube, a solution of 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol (200 mg, 1 .05 mmol) in DCM (2 ml). To the solution, DAST (254 mg, 1.58 mmol) was added at 0 °C. The resulting solution was stirred for 2 h at RT. The residue was eluted from silica gel with DCM/MeOH (8:1). This resulted in 85 mg (42%) of the title compound as a yellow solid. MS-ESI: 193 (M+1). Scheme 35: Intermediate 56

3-((tert-butyldimethylsilyl)oxy)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

[002199] In a 100 ml round bottom flask, 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol (1.0 g, 5.26 mmol) in DMF (10 ml, 129 mmol). To the stirred solution, DBU (1.6 g, 11 mmol) and TBSCl (1.58 g, 11 mmol) were added. The resulting solution was stirred for 4 h at RT. The reaction was then stopped with the addition of 1 ml of water. The resulting solution was extracted with 3x15 ml of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was eluted from silica gel with EtOAc/PE (41%). This resulted in 1.07 g (67%) of the title compound as a white solid. Scheme 36: Intermediate 57

8-Amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide Step 1: (1,2,3,5,6,7-hexahydrodicyclopenta[b ,e]pyridin-8-yl) tert-butyl carbamate

[002200] In a 50 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8- amine (500 mg, 2.87 mmol) in THF (3 ml). This was followed by the addition of LiHMDS (1M in THF, 5.7 ml, 5.7 mmol) drip with stirring at 80°C. The mixture was stirred for an additional 1 h. Thereto was added (Boc)2O (1.88 g, 8.61 mmol) at 80°C. The resulting solution was stirred for 16 h at 80 °C in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x30 ml of EtOAc and concentrated. The residue was eluted from silica gel with DCM/MeOH (15:1). This resulted in 300 mg (38%) of the title compound as a dark yellow solid. MS-ESI: 275(M+1). Step 2: 8-((tert-butoxycarbonyl)amino)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide

[002201] In a 50 ml round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin- tert-Butyl 8-yl)carbamate (900 mg, 3.28 mmol) in DCM (15 ml). To the above solution, m-CPBA (1.13 g, 6.56 mmol) was added. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x30 ml of EtOAc and concentrated. The residue was eluted from silica gel with DCM/MeOH (15:1). This resulted in 750 mg (78.7%) of the title compound as a dark yellow solid. MS-ESI: 291(M+1). Step 3: 8-Amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide

[002202] In a 50 ml round bottom flask, purged and maintained with an inert atmosphere of nitrogen, 8-((tert-butoxycarbonyl)amino)-1,2,3,5 4-oxide was placed, 6,7-hexahydrodicyclopenta[b,e]pyridine (550 mg, 1.89 mmol) in DCM (8.0 ml) and TFA (4.0 ml). The resulting solution was stirred for 20 min at RT. The pH value of the solution was adjusted to 7 with Na2CO3. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (8:1). This resulted in 184 mg (51%) of the title compound as a yellow solid. MS-ESI: 191(M+1). Scheme 37: Intermediate 58 4,6-Diisopropyl-2-(trifluoromethyl)pyrimidin-5-amine Step 1: 4-Bromo-2-(trifluoromethyl)pyrimidin-5-amine

[002203] In a 100 ml round bottom flask, purged and maintained with an inert atmosphere of nitrogen, 2-

(trifluoromethyl)pyrimidin-5-amine (2.0 g, 12.26 mmol) in acetonitrile (20 ml). To this stirred solution, NBS (2.62 g, 14.7 mmol) was added. The resulting solution was stirred for 12 h at RT. The resulting solution was diluted with 40 ml of water, extracted with 2x30 ml of DCM and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:50 to 1:20). This resulted in 1.6 g (54%) of the title compound as a brown solid. MS-ESI: 242/244 [M+1] Step 2: 4-(Prop-1-en-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine

[002204] In a 100 ml round bottom flask, purged and maintained with an inert atmosphere of nitrogen, 4-bromo-2-(trifluoromethyl)pyrimidin-5-amine (1.6 g, 6.61 mmol) in dioxane (20 ml). This was followed by the addition of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.44 g, 8.57 mmol), Pd (dppf)Cl2 (242mg, 0.33mmol) and Cs2CO3 (3.23g, 9.92mmol). The resulting solution was stirred for 14 h at 100 °C in an oil bath. The resulting solution was diluted with 40 ml of water. The resulting solution was extracted with 3x30 ml of DCM and concentrated. The residue was eluted from silica gel with EtO-Ac/PE (1:5). This resulted in 1.1 g (82%) of the title compound as a brown solid. MS-ESI: 204 [M+1]. Step 3: 4-Isopropyl-2-(trifluoromethyl)pyrimidin-5-amine

[002205] In a 100 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-(prop-1-en-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine was placed (1.2 g, 5.91 mmol) in MeOH (20 ml), to the stirred solution was added Pd/C (10% by weight, 200 mg). The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred 16 h at RT under hydrogen. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. This resulted in 1.1 g (91%) of the title compound as a brown solid. MS-ESI: 206 [M+1]. Step 4: 4-Bromo-6-isopropyl-2-(trifluoromethyl)pyrimidin-5-amine

[002206] In a 50 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-(propan-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine (1.1 g, 5.36 mmol) in acetonitrile (20 ml), to this solution was added NBS (1.15 g, 6.46 mmol) in portions with stirring. The resulting solution was stirred for 12 h at RT. The resulting solution was diluted with 40 ml of water. The resulting solution was extracted with 2x30 ml of DCM and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:40 to 1:30). This resulted in 1.0 g (66%) of the title compound as a brown solid. MS-ESI: 284/286 [M+1]. Step 5: 4-Isopropyl-6-(prop-1-en-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine

[002207] In a 100 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-bromo-6-(propan-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine was placed (1.2 g, 4.2 mmol) in dioxane (20 ml) and H 2 O (4 ml). To the stirred solution, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.92 g, 5.5 mmol), Pd (dppf)Cl2 (155mg, 0.21mmol) and Cs2CO3 (2.06g, 6.3mmol). The resulting solution was stirred for 16 h at 100 °C in an oil bath. The resulting mixture was concentrated. The residue was applied to silica gel with EtOAc/PE (1:3). This resulted in 870 mg (84%) of the title compound as a yellow solid. Step 6: 4,6-Diisopropyl-2-(trifluoromethyl)pyrimidin-5-amine

[002208] In a 50 ml round bottom flask, purged and maintained with an inert atmosphere of H2, 4-isopropyl-6-(prop-1-en-2-yl)-2-(trifluoromethyl) was placed pyrimidin-5-amine (870 mg, 3.5 mmol) in MeOH (20 ml). To the stirred solution, Pd/C (10% by weight, 125 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred 16 h at RT under hydrogen. The solids were removed by filtration. The resulting mixture was concentrated in vacuo. This resulted in 830 mg (99.2%) of the title compound as a yellow oil. Scheme 38: Intermediate 59

No THE The No.

HF phenyl 5-fluoro-2,4-diisopropylpyridin-3-ylcarbamate

[002209] In a 50 ml round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 5-fluoro-2,4-diisopropylpyridin-3-amine (200 mg, 1.02 mmol) in THF (10 ml). To the stirred solution, NaH (60% by weight of oil dispersion, 122 mg, 3.06 mmol) was added at 0 °C. The resulting solution was stirred for 10 min at RT. Then, phenyl chloroformate (160 mg, 1.02 mmol) was added at 0 °C. The resulting solution was allowed to react, with stirring, for a further 20 h at RT. The reaction mixture was used in the next step directly without further purification. Table 11. The Intermediates in the following Table were prepared using similar procedures to convert intermediate 29 to Intermediate 59 shown in Scheme 38 from suitable starting materials.

Sharply cooled Interme- Structure IUPAC name made with MeOH, daily # Exact Mass [M+H]+ 2,4-di- Interme- O isopropylpyridin-3- N 237 daily 60 O N ylcarbamate of

H phenyl (1,2,3,5,6,7-hexahydrodicyclopent-Interme-O N ta[b,e]pyridin-8-233 daily 61 O N H yl)carbamate Scheme 39: Intermediate 62

HN N Cl O Cl

2,2,2-Trichloroethyl Cl(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

[002210] 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine ( 6.7 g, 38 mmol) in THF (500 ml). To the above solution, DIEA (9.92 g, 76.9 mmol) was added dropwise at RT. Then, 2,2,2-trichloroethyl chloroformate (16 g, 76.9 mmol) was dropped into the reaction solution at 0 °C. The resulting solution was stirred for 16 h at RT.

The resulting mixture was concentrated.

The residue was eluted from silica gel with EtOAc/hexane (1:4). This resulted in 7.3 g (54.4%) of the title compound as a yellow solid.

MS-ESI: 349/351 (M+1). Table 12. The Intermediates in the following Table were prepared using similar procedures to convert intermediate 33 to Intermediate 62 shown in Scheme 39 from suitable starting materials.

Interme- Structure Name IUPAC Exact Mass Daily No. [M+H]+ (3,3-dimethyl-1,2,3,5,6,7-hexa-Intermehydrodicyclopen- 377/379 daily 63 ta[b,e 2,2,2-Trichloroethyl]pyridin-8-yl)carbamate (1',5',6',7'-tetrahydro-2'H-spiro[cyclopropane-1,3'-Intermedicyclopenta[ daily b,e]pyridin]-361/363 64 Trichloromethyl 8'-yl)carbamate (3-ethyl-2-methyl-6,7-dihydro-5H-Intermecyclopenta[b]pyridin-4 - 351/353 daily 65 2,2,2-Trichloroethyl (3-isopropyl-2-methyl-6,7-dihydro-5H-Intermecyclopenta[b]pyridin-4-365/367 yl)carbamate daily 66 2,2,2-trichloroethyl yl)carbamate

Interme- Structure Name IUPAC Exact Mass Daily No. [M+H]+ (3-Methyl-1,2,3,5,6,7-hexahydrodicyclopen-Intermeta[b,e]pyridin-8-349/ 351 daily 67 trichloromethyl (2-cyclopropyl-3-methyl-6,7-dihydro-5H-Intermecyclopenta[b]pyridin-4-363/365 daily 68 yl)carbamate daily 68 yl)carbamate 2,2-Trichloroethyl (2-cyclopropyl-6,7-dihydro-Interme-5H-cyclopenta[b]pyridin-4-349/351 daily 69-yl)carbamate (3-( (tert-butyldimethylsilyl)oxy)-1,2,3,5,6,7-hexa-Intermehydrodicyclopen- 479/481 daily 70 2,2,2 ta[b,e]pyridin-8-yl)carbamate - 2,2,2-Trichloroethyl (3,5-dimethyl-1,2,3) trichloroethyl (4,6-diisopropyl-2-Interme-(trifluoromethyl)pyrimidin-5-daily 71yl)carbamate 2,2,2-Trichloroethyl ta[b,e]pyridin-8-yl)carbamate daily

Interme- Structure Name IUPAC Exact Mass Daily No. [M+H]+ (2-cyclopropyl-3-ethyl-6,7-dihydro-5H- Intermecyclopenta[b]pyridin-4- 377/379 daily 73 il 2,2,2-Trichloroethyl (2-isopropyl-6,7-dihydro-Interme-5H-cyclopenta[b]pyridin-4-351/353 daily 74yl)carbamate of 2,2,2- 2,2,2-Trichloroethyl trichloroethyl (3-fluoro-1,2,3,5,5,6,7-hexa-Intermehydrodicyclopen- 367/369 daily 75 75 ta[b,e]pyridin-8-yl)carbamate Scheme 40: Intermediate 76 N-(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide

[002211] In a 50 ml 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed

each 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (2.0 g, 11.5 mmol) in DMF (22 mL). To the stirred solution, NaH (60% by weight of oil dispersion, 1.38 g, 34.5 mmol) was added at 0 °C.

The resulting solution was stirred for 30 min at RT.

Then, CDI (2.79 g, 17.3 mmol) was added to the solution.

The resulting solution was stirred for 1 h at RT.

The raw product was used directly without finishing.

Table 13. The Intermediates in the following Table were prepared using similar procedures to convert intermediate 33 to Intermediate 76 shown in Scheme 40 from suitable starting materials.

Interme- Structure Name IUPAC Daily No. cooled with MeOH, Exact Mass [M+H]+ N-(3-methyl-1,2,3,5,6,7-hexa- Intermehydrodicyclopent-265 daily 77 ta[ b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide

N-(3,5-di-Intermeisopropylpyridin-4-yl)-1H- daily 78 imidazole-1-carboxamide

N-(2,3,5,6,7,8-hexahydro-1H-Intermecyclopenta[b]quinolin-9-247 daily 79yl)-1H-imidazol-1-carboxamide N-(3,3 -dimethyl-1,2,3,5,6,7-hexa-Intermehydrodicyclopentane 80 ta[b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide

Interme- Structure Name IUPAC Roughly daily # cooled with MeOH, Exact Mass [M+H]+ N-(2-methyl-1,2,3,5,6,7-hexa- Intermehydrodicyclopent-247 daily 81 ta[ b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide N-(1-methyl-1,2,3,5,6,7-hexa-Intermehydrodicyclopentane 247 82 ta[b, e]pyridin-8-yl)-1H-imidazole-1-carboxamide N-(2,2-dimethyl-1,2,3,5,6,7-hexa-Intermehydrodicyclopentane 261 83 ta[b, e]pyridin-8-yl)-1H-imidazole-1-carboxamide 8-(1H-imidazole-1-Intermecarboxamido)-4-oxide daily 84 1,2,3,5,6,7-hexa - hydrodicyclopenta[b,e]pyridine

N-(2,3,5,6-Intermetetramethylpyridin-4-yl)-1H-daily 85 imidazole-1-carboxamide

N-(2-propyl-6,7-dihydro-Interme-5H-cyclopenta[b]pyridin-235 daily 86 4-yl)-1H-imidazole-1-carboxamide

Scheme 41: Intermediate 87 2-Fluoro-4-isocyanate-3,5-diisopropylpyridine

[002212] In a 50 ml round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 2-fluoro-3,5-diisopropylpyridin-4-amine (100 mg, 0.51 mmol) in THF (20 ml). To the stirred solution, TEA (155 mg, 1.53 mmol) and BTC (75 mg, 0.26 mmol) were added. The resulting solution was stirred for 2 h at 60 °C in an oil bath. The resulting mixture was concentrated. This resulted in 150 mg of crude title product as a gray solid. Table 14. The Intermediates in the following Table were prepared using similar procedures to convert intermediate 30 to Intermediate 87 shown in Scheme 41 from suitable starting materials.

Interme- Structure Name IUPAC Roughly daily No. cooled with MeOH, Exact Mass [M+H]+

5-fluoro-3-isocyanato-Interme-2,4-di-daily 88 isopropylpyridine

8-isocyanate-3-methyl-Interme-1,2,3,5,6,7-hexa-daily 89 hydrodicyclopenta[b,e]pyridine

4-isocyanate-3-Intermeisopropyl-2-phenyl-6,7- daily 90 dihydro-5H-cyclopenta[b]pyridine

3-Ethyl-4-isocyanate-2-Intermephenyl-6,7-dihydro-5H- daily 91 cyclopenta[b]pyridine

4-Isocyanato-3-methyl-Interme-2-phenyl-6,7-dihydro-daily 92 5H-cyclopenta[b]pyridine

4-isocyanate-2-phenyl-Interme-6,7-dihydro-5H- daily 93 cyclopenta[b]pyridine

4-isocyanate-2,3-Intermedimethyl-6,7-dihydro-daily 94 5H-cyclopenta[b]pyridine

Interme- Structure Name IUPAC Roughly daily No. cooled with MeOH, Exact Mass [M+H]+

2-ethyl-4-isocyanate-Interme-6,7-dihydro-5H- daily 95 cyclopenta[b]pyridine

8'-Isocyanato-1',5',6',7'-tetrahydro-2'H- Intermespiro[cyclopropane-daily 96 1,3'-dicyclopenta[b,e]pyridine]

2-cyclopropyl-4-Intermeisocyanato-3-methyl-daily 97 6,7-dihydro-5H-cyclopenta[b]pyridine

Scheme 42

Intermediate 98

2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine

Step 1: 2-Oxo-N-phenylcyclopentane-1-carboxamide

[002213] In a 250 ml round bottom flask, purged and maintained under an inert atmosphere of nitrogen, methyl 2-oxocyclopentane-1-carboxylate (10 g, 70 mmol) in xylene (100 ml) was placed at stirred solution, added aniline (6.6 g, 71 mmol) was added. The resulting solution was stirred for 6 h at 140 °C in an oil bath. The resulting mixture was concentrated. This resulted in 13.4 g (93%) of the title compound as a brown oil. MS-ESI: 204 (M+1). Step 2: 2,3-dihydro-1H-cyclopenta[c]quinolin-4(5H)-one

[002214] In a 250 ml round bottom flask was placed 2-oxo-N-phenylcyclopentane-1-carboxamide (13.4 g, 65.7 mmol) in H2SO4 (50 ml). The resulting solution was stirred overnight at 30 °C in an oil bath. The resulting solution was carefully poured into 1.0 L of H2O. The pH value of the solution was adjusted to 7 with aqueous NaOH (10% by weight). Solids were removed by filtration. The resulting solution was extracted with 2x250 ml of ethyl acetate and dried over anhydrous sodium sulfate and concentrated. This resulted in 3.7 g of the title compound as a dark yellow solid. MS-ESI: 186 (M+1). Step 3: 4-Chloro-2,3-dihydro-1H-cyclopenta[c]quinolone

[002215] In a 100 ml round bottom flask, 2,3-dihydro-1H-cyclopenta[c]quinolin-4(5H)-one (950 mg, 5.13 mmol) in POCl3 (20 ml, 215 mmol). The resulting solution was stirred overnight at 80 °C in an oil bath. The resulting mixture was concentrated. The resulting solution was diluted with 50 ml of ethyl acetate. The resulting mixture was washed with 3x25 ml of H2O. The mixture was dried over anhydrous sodium sulfate and then concentrated. This resulted in 975 mg (93%) of the title compound as a dark yellow solid. MS-ESI: 204 (M+1). Step 4: N-(4-methoxybenzyl)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine

[002216] In a 100 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-chloro-2,3-dihydro-1H-cyclopenta[c]quinoline (780 mg, 3 .83 mmol) in dioxane (25 ml), to the above solution was added 1-(4-methoxyphenyl)methanamine (788 mg, 5.74 mmol), Pd2(dba)3 (351 mg, 0.38 mmol), DavePhos (151 mg, 0.38 mmol) and t-BuOK (1.29 g, 11.5 mmol). The resulting solution was stirred for 4 h at 100 °C in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 768 mg (66%) of the title compound as a dark yellow solid. MS-ESI: 304 (M+1). Step 5: 2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine

[002217] In a 50 ml round bottom flask was placed N-(4-methoxybenzyl)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine (800 mg, 2.63 mmol ) in CHCl 3 (15 ml), to the above solution, TFA (17.1 ml, 150 mmol) was added dropwise. The resulting solution was stirred for 4 h at 65 °C in an oil bath. The resulting mixture was concentrated. The resulting solution was diluted with ?? ml of ethyl acetate. The pH value of the solution was adjusted to 8 with the Na2CO3 solution (10% by weight). The resulting solution was extracted with 2x150 ml of ethyl acetate, and the organic layers combined and concentrated. This resulted in 750 mg of the crude title compound as a yellow solid. MS-ESI: 185 (M+1). Intermediate 99

H Cl3C O N N

2,2,2-Trichloroethyl 2,3-dihydro-1H-cyclopenta[c]quinolin-4-ylcarbamate

[002218] Intermediate 99 was prepared using similar procedures to convert Intermediate 33 to Intermediate 62 shown in Scheme 39 from Intermediate 98. MS-ESI: 359/361 (M+1).

[002219] Schemes of Sulfonimidoylamide Intermediates: Schemes 43 to 67 illustrate the preparation of sulfonimidoylamide intermediates. Scheme 43: Intermediate 100 N'-(tert-butyldimethylsilyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-sulfonimidamide Step 1: 3-Nitro-1-(2,2,2-trifluoroethyl )-1H-pyrazole

[002220] To a stirred solution of 3-nitro-1H-pyrazole (10 g, 88.5 mmol) in DMF (100 ml) in a 250 ml round bottom flask was added Cs2CO3 (57.7 g, 177 mmol) at RT, followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (20.5 g, 88.5 mmol) dropwise at 0°C. The resulting solution was stirred for 2 h at RT. Solids were removed by filtration. The resulting mixture was diluted with 200 ml of EtOAc, then washed with 3x300 ml of water. The organic layer was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 10.5 g (61%) of the title compound as a yellow solid. MS-ESI: 196 (M+1). Step 2: 1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-amine

[002221] To a stirred solution of 3-nitro-1-(2,2,2-trifluoroethyl)-1H-

pyrazole (7.2 g, 36.9 mmol) in MeOH (70 ml) in a 100 ml round bottom flask under nitrogen, Pd/C (10 wt%, 720 mg) was added in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen with a balloon. The solid was removed by filtration. The resulting mixture was concentrated under reduced pressure. This resulted in 5.8 g (95%) of the title compound as a yellow solid. MS-ESI: 166.1 (M+1). Step 3: 1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-sulfonyl chloride

[002222] To a stirred solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine (5.0 g, 30.3 mmol) in HCl (6 M, 50 ml) in a flask 250 ml 3-neck round bottom, NaNO 2 (2.5 g, 36.4 mmol) in H 2 O (20 ml) was added dropwise with stirring at 0 °C for 10 min. The resulting solution was stirred for 30 min at 0 °C, this solution was designated solution A. Then, CuSO4 (14.5 g, 90.8 mmol) was added to a 500 ml single-necked round bottom flask. with AcOH (90 ml) as the solvent. Then SO2 (g) was bubbled into the solution with stirring at RT for 20 min, this solution was designated solution B. To solution B, solution A was added dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at RT. The residue was diluted with 200 ml of water and extracted with 3x200 ml of DCM. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 5.6 g (crude product) of the title compound as a yellow oil. Step 4: 1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-sulfonamide

[002223] To a stirred solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-sulfonyl chloride solution (crude product; from Step above) in DCM (100 ml) in a bottom flask 250 ml round, NH3 (g) was bubbled through at 0 °C for 10 min. The resulting solution was stirred for 2 h at RT. The solution was concentrated under vacuum. The crude product was eluted

of silica gel with DCM/MeOH (95:5). This resulted in 4.7 g (67% over two steps) of the title compound as a yellow solid. MS-ESI: 230 (M+1). Step 5: N-(tert-butyldimethylsilyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-sulfonamide

[002224] To a stirred solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-sulfonamide (3.2 g, 14 mmol) in DCM (100 ml) in a 250 µl round bottom flask ml, DIEA (7.2 g, 55.7 mmol) was added at RT, then TBSCl (3.2 g, 20.9 mmol) was added in portions at RT. The resulting solution was stirred for 2 h at RT. The resulting mixture was washed with 5x100 ml of H2O. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 4.0 g (83%) of the title compound as a yellow solid. MS-ESI: 344 (M+1). Step 6: N'-(tert-butyldimethylsilyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-sulfonimidamide

[002225] To a stirred solution of PPh3Cl2 (15.5 g, 46.6 mmol) in CHCl3 (100 mL) in a 250 mL 3-necked round bottom flask under nitrogen was added DIEA (7.51 g, 58.2 mmol) by drip with stirring at 0 °C. After stirring for 10 min at RT, to the above was added a solution of N-(tert-butyldimethylsilyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-sulfonamide (4.0 g, 11, 7 mmol) in CHCl 3 (30 ml) by dropping with stirring at 0 °C. The resulting solution was allowed to react for 30 min at 0 °C. To the mixture, NH3 (g) was bubbled through with stirring at 0 °C for 15 min. The resulting solution was stirred for 2 h at RT. The reaction was then stopped with the addition of 200 ml of water. The resulting solution was extracted with 3x200 ml of DCM, and the organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (95:5). This resulted in 1.8 g (45%) of the title compound as a white solid. MS-ESI: 343 (M+1).

Scheme 44: Intermediate 101

The N TBS

Y N NH2

N N'-(tert-butyldimethylsilyl)-1-isopropyl-4-methyl-1H-pyrazol-3-sulfonimidamide Step 1: 1-Isopropyl-4-methyl-3-nitro-1H-pyrazole

[002226] To a stirred solution of 4-methyl-3-nitro-1H-pyrazole (10 g, 78.7 mmol) in DMF (100 ml) in a 250 ml round bottom flask under nitrogen was added K2CO3 ( 32.6 g, 236 mmol) in portions, then 2-bromopropane (19.4 g, 157 mmol) was added dropwise at RT. The resulting solution was stirred for 2 days at RT. Solids were removed by filtration. The resulting mixture was diluted with 100 ml of EtOAc. The resulting mixture was washed with 5x200 ml of water. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 12.3 g (92%) of the title compound as a yellow oil. MS-ESI: 170 (M+1).

[002227] Steps 2 to 7 used similar procedures to convert compound 182 to intermediate 100 shown in Scheme 43 to provide intermediate 101 from compound 188. MS-ESI: 317 (M+1). Table 25. The Intermediates in the following table were prepared using similar procedures to convert compound 187 to

Intermediate 101 shown in Scheme 44 from suitable starting materials. Intermediate Structure IUPAC Name Exact Mass # [MH]-N'-(tert-Intermediate-butyldimethylsilyl)-1-ethyl-289 102 1H-pyrazol-3-sulfonimidamide N'-(tert-Intermediate-butyldimethylsilyl)-1-275 103 methyl-1H-pyrazol-3-sulfonimidamide Scheme 45: Intermediate 104 N'-(tert-butyldimethylsilyl)-1-(difluoromethyl)-1H-pyrazol-4-sulfonimidamide Step 1: 1-(Difluoromethyl)-4-nitro -1H-pyrazole

[002228] To a stirred solution of 4-nitro-1H-pyrazole (15 g, 133 mmol) in DMF (150 ml) in a 500 ml round bottom flask,

Na 2 CO 3 (21.1 g, 199 mmol) and sodium 2-chloro-2,2-difluoroacetate (24.3 g, 159 mmol) were added at RT. The resulting solution was stirred for 3 h at 90 °C. The reaction was then quenched by the addition of 100 ml of water. The resulting solution was extracted with 2x100 ml of EtOAc, and the organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 16 g (97%) of the title compound as a red liquid. MS-ESI: 164 (M+1).

[002229] Steps 2 to 7 used similar procedures to convert compound 182 to intermediate 100 shown in Scheme 43 to provide intermediate 104 from compound 195. MS-ESI: 311 (M+1). Scheme 46: Intermediate 105 N'-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide

[002230] Step 1 used similar procedures to convert compound 187 to compound 188 shown in Scheme 44 to provide compound 202 from compound 201. MS-ESI: 198

(M+1).

[002231] Steps 2 to 3 used similar procedures to convert compound 183 to compound 185 shown in Scheme 43 to provide compound 204 from compound 202. MS-ESI: 262 (M+1). Step 4: 4-(hydroxymethyl)-1-isopropyl-1H-pyrazol-3-sulfonamide

[002232] To a stirred solution of ethyl 1-isopropyl-3-sulfamoyl-1H-pyrazole-4-carboxylate (1.5 g, 5.3 mmol) in THF (10 ml) in a 100 ml round bottom flask under nitrogen, BH3-THF (1M, 6.4 ml, 6.4 mmol) was added dropwise at 0 °C in a water/ice bath. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched by the addition of 50 ml of water and extracted with 2x100 ml of EtOAc, the organic layers were combined and dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 1.1 g (94%) of the title compound as a white solid. MS-ESI: 220 (M+1). Step 5: N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-1-isopropyl-1H-pyrazol-3-sulfonamide

[002233] To a stirred solution of 4-(hydroxymethyl)-1-isopropyl-1H-pyrazol-3-sulfonamide (1.2 g, 6.0 mmol) in THF (20 ml) in a 250 µl round bottom flask ml under nitrogen, NaH (60% by weight of mineral oil dispersion, 867 mg, 36 mmol) was added in portions at 0 °C, followed by the addition of TBSCl (1.8 g, 12.0 mmol) in small portions. at 0°C. The resulting solution was stirred for 3 h at RT. The resulting mixture was quenched by the addition of 50 ml of water and extracted with 2x100 ml of EtOAc, and the organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. This resulted in 1.2 g (crude product) of the title compound as a yellow solid. MS-ESI: 448 (M+1).

[002234] Steps 6 to 7 used similar procedures to convert compound 186 to Intermediate 100 shown in Scheme 43 to provide intermediate 105 from compound 206. MS-ESI: 447 (M+1). Scheme 47: Intermediate 106 N'-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide

[002235] Steps 1 to 4 used similar procedures to convert compound 187 to compound 191 shown in Scheme 44 to provide compound 212 from compound 208. MS-ESI: 246 (M-1). Step 5: 5-(hydroxymethyl)-1-isopropyl-1H-pyrazol-3-sulfonamide

[002236] To a stirred solution of methyl 1-isopropyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (2.4 g, 9.7 mmol) in ethanol (150 ml) in a 500 µl round bottom flask ml under nitrogen was added

NaBH4 (1.84 g, 48.5 mmol) in portions at 0 °C. The resulting solution was stirred overnight at RT. The reaction was quenched by the addition of saturated NH4Cl (aq.) (20 ml) at 0 °C. The resulting mixture was concentrated under reduced pressure. The mixture was adjusted to pH 7 with HCl (aq.). The resulting mixture was extracted with 3x50 ml of EtOAc. The combined organic layer was washed with water (3x20ml) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 1.5 g (70%) of the title compound as a pale yellow solid. MS-ESI: 220 (M+1).

[002237] Steps 6 to 8 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 106 from compound 216. MS-ESI: 447 (M+1). Scheme 48: Intermediate 107 N'-(tert-butyldimethylsilyl)-4-chloro-1-isopropyl-1H-pyrazol-3-sulfonimidamide Step 1: 1-Isopropyl-1H-pyrazol-3-amine

[002238] To a stirred solution of isopropylhydrazine hydrochloride (60 g, 546 mmol) in H2O (600 mL) in a round-bottomed flask of

1 L, K2CO3 (226 g, 1.64 mol) was added in portions at 0°C. The resulting solution was stirred for 2 h at RT. Then, 2-chloroacrylonitrile (28 g, 328 mmol) was added to the solution dropwise at 0 °C. The resulting solution was stirred overnight at 50°C. The resulting solution was extracted with 3x500 ml of EtOAc. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 36 g (90%) of the title compound as a yellow oil. MS-ESI: 126 (M+1). Step 2: 4-Chloro-1-isopropyl-1H-pyrazol-3-amine

[002239] To a stirred solution of 1-isopropyl-1H-pyrazol-3-amine (30 g, 240 mmol) in ACN (300 ml) in a 500 ml round bottom flask under nitrogen was added NCS (32 g , 240 mmol) in portions. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched by the addition of 500 ml of water and extracted with 3x500 ml of EtOAc, and the organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 25 g (65%) of the title compound as a dark yellow solid. MS-ESI: 160 (M+1).

[002240] Steps 3 to 7 used similar procedures to convert compound 183 to Intermediate 100 shown in Scheme 43 to provide Intermediate 108 from compound 218. MS-ESI: 337 (M+1). Scheme 49: Intermediate 108 N'-(tert-butyldimethylsilyl)-1-isopropyl-1H-imidazol-4-sulfonimidamide

[002241] Steps 1 to 3 used similar procedures to convert compound 185 to Intermediate 100 shown in Scheme 43 to provide Intermediate 108 from compound 223. MS-ESI: 303 (M+1). Scheme 50: Intermediate 109 N'-(tert-butyldimethylsilyl)-1-(4-fluorophenyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-sulfonimidamide Step 1: 1-(4-fluorophenyl )-3-nitro-1H-pyrazole-5-carboxylate methyl

[002242] To a stirred solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (10 g, 58.4 mmol) in DCM (200 ml) in a 500 ml round bottom flask was added acid ( 4-fluorophenyl)boronic acid (24.5 g, 175 mmol) and pyridine (9.25 g, 117 mmol), followed by the addition of Cu(OAc) 2 (15.9 g, 88 mmol) at RT. The resulting solution was stirred for 16 h at RT. Solids were removed by filtration. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel.

ca with EtOAc/PE (1:3). This resulted in 6.4 g (41%) of the title compound as an off-white solid. MS-ESI: 266 (M+1).

[002243] Steps 2 to 4 used similar procedures to convert compound 182 to compound 185 shown in Scheme 43 to provide compound 230 from compound 227. MS-ESI: 298 (M-1). Step 5: 1-(4-Fluorophenyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-sulfonamide

[002244] To a stirred solution of methyl 1-(4-fluorophenyl)-3-sulfamoyl-1H-pyrazole-5-carboxylate (2.8 g, 9.4 mmol) in THF (100 mL) in a flask 250 ml round bottom under nitrogen, MeMgBr in THF (3 M, 16 ml, 48 mmol) was added by dropping at 0 °C in an ice bath. The resulting solution was stirred for 2 h at 0 °C. The reaction was then quenched by the addition of 20 ml of water/ice. The resulting solution was extracted with 3x100 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 1.2 g (43%) of the title compound as a yellow solid. MS-ESI: 300 (M+1).

[002245] Steps 6 to 7 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 109 from compound 231. MS-ESI: 432 (M+1).

Scheme 51: Intermediate 110 N'-(tert-butyldimethylsilyl)-1-phenyl-1H-pyrazol-3-sulfonimidamide

[002246] Steps 1 to 4 used similar procedures to convert compound 226 to compound 230 shown in Scheme 50 to provide compound 237 from compound 233. MS-ESI: 222 (M-1).

[002247] Steps 5 to 7 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 110 from compound 237. MS-ESI: 337 (M+1).

Scheme 52: Intermediate 111 N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide

[002248] Steps 1 to 4 used similar procedures to convert compound 187 to compound 191 shown in Scheme 44 to provide compound 244 from compound 240. MS-ESI: 246 (M-1).

[002249] Steps 5 to 8 used similar procedures to convert compound 230 to Intermediate 109 shown in Scheme 50 to provide Intermediate 111 from compound 244. MS-ESI: 361 (M+1). Scheme 53:

Intermediate 112 N'-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide Step 1: 6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine

[002250] To a stirred solution of 1,2-dihydro-3H-pyrazol-3-one (42 g, 500 mmol) in DMF (500 mL) in a 1 L round bottom flask under nitrogen was added K2CO3 (138 g, 1.0 mol) in portions at RT. Followed by the addition of 1,3-dibromopropane (111 g, 550 mmol) dropwise at RT. The resulting mixture was stirred for 16 h at 130 °C. Insoluble matter was removed by filtration, the filtrate was poured into 1.5 L of water and extracted with 3x500 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with petroleum ether/EtOAc (20:1) to provide 24.8 g (40%) of the title compound as a yellow solid. MS-ESI: 125 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 2.0 Hz, 1H), 5.48 (d, J = 2.0 Hz, 1H), 4.28 (t, J = 5.2 Hz, 2H), 4.18 (t, J = 6.2 Hz, 2H), 2.30-2.23 (m, 2H). Step 2: 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride

[002251] A solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (24 g, 194 mmol) in chlorosulfonic acid (143 ml) in a round bottom flask with 3 500 ml bottlenecks under nitrogen, it was stirred for 16 h at 80 °C. The reaction mixture was poured into 1.5 L of water/ice very slowly and extracted with 3x500 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was washed with 300 ml of PE. This resulted in 28.1 g (65.0%) of the title compound as a yellow solid.

MS-ESI: 223/225 (M+1). Step 3: 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

[002252] To a stirred solution of ammonia (30% by weight, 40 ml) in a 3-neck 250 ml round bottom flask under nitrogen was added 6,7-dihydro-5H-pyrazole chloride [5,1-b][1,3]oxazine-3-sulfonyl (28 g, 126 mmol) in THF (80 ml) dripped at RT. The resulting solution was stirred for 16 h at 60 °C. The organic solvent was removed and concentrated under reduced pressure. The water layer was extracted with 3x100 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was eluted from a silica gel column with PE/EtOAc (1:1). This resulted in 16.9 g (66%) of the title compound as a pale yellow solid. MS-ESI: 202 (M-1). 1H NMR (300 MHZ, DMSO-d6): δ 7.47 (s, 1H), 7.08 (s, 2H), 4.40 (t, J = 5.1 Hz, 2H), 4.10 ( t, J = 6.0 Hz, 2H), 2.25-2.15 (m, 2H).

[002253] Steps 4 to 5 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 112 from compound 251. MS-ESI: 317 (M+1). Scheme 54: Intermediate 113

N'-(tert-butyldimethylsilyl)-4-(1-(tert-butyldimethylsilyloxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Step 1: 1-(2-Aminothiazol-4- (yl)ethanol

[002254] To a stirred solution of 1-(2-aminothiazol-4-yl)ethan-1-one (5.6 g, 39.4 mmol) in MeOH (100 mL) in a 3-necked round bottom flask of 500 ml under nitrogen, NaBH4 (2.24 g, 59.2 mmol) was added in portions below 5 °C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 500 ml of water/ice. The resulting solution was extracted with 3x300 ml of EtOAc. The combined organic layer was washed with 3x300 ml of brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 5.68 g (99%) of the crude title compound as a pale yellow solid. MS-ESI: 145 (M+1). Step 2: 1-(2-Bromothiazol-4-yl)ethanol

[002255] To a stirred solution of 1-(2-aminothiazol-4-yl)ethanol (5.68 g, crude product) in ACN (100 ml) in a 250 ml round bottom flask under nitrogen was added CuBr (8.48 g, 59.1 mmol) and tert-butyl nitrite (6.09 g, 59.1 mmol). The resulting solution was stirred for 2 h at 65 °C. Insoluble matter was removed by filtration, and the filtrate was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 3.03 g (37% over two steps) of the title compound as a pale yellow solid. MS-ESI: 208 (M+1). Step 3: 2-Bromo-4-(1-(tert-butyldimethylsilyloxy)ethyl)thiazole

[002256] To a stirred solution of 1-(2-bromothiazol-4-yl)ethanol (4.0 g, 19.2 mmol) in THF (70 ml) in a 250 ml round bottom flask under nitrogen was NaH (60% by weight, mineral oil dispersion, 1.54 g, 38.4 mmol) is added at 0°C. This was followed by the addition of a solution of TBSCl (5.80 g, 38.4 mmol) in THF (10 ml) by dripping at 0 °C over 3 min. The resulting solution was stirred for 10 h at RT. The resulting solution was diluted with H2O (100 ml) and extracted with

3x100 ml of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 7.0 g (crude product) of the title compound as a pale yellow oil. MS-ESI: 322 (M+1). Step 4: 2-(4-(1-(tert-butyldimethylsilyloxy)ethyl)thiazol-2-yl)propan-2-ol

[002257] To a stirred solution of 2-bromo-4-(1-(tert-butyldimethylsilyloxy)ethyl)thiazole (5.2 g, 16.1 mmol) in THF (100 ml) in a round-bottomed flask with three 500 ml bottlenecks under nitrogen, n-BuLi in hexane (2.5 M, 16 ml, 40.3 mmol) was added dropwise at -70 °C in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 50 min at -70 °C. Then, propan-2-one (9.37 g, 161 mmol) was added dropwise to the above solution at -70 °C. The resulting solution was allowed to react with stirring for a further 60 min at RT. The reaction was then stopped with the addition of 100 ml of sat. The resulting solution was extracted with 3x200 ml of EtOAc, and the organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:30). This resulted in 3.03 g (62%) of the title compound as a white solid. MS-ESI: 302 (M+1). Step 5: 4-(1-(tert-butyldimethylsilyloxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002258] To a stirred solution of 2-(4-(1-(tert-butyldimethylsilyloxy)ethyl)thiazol-2-yl)propan-2-ol (300mg, 1.0mmol) in THF (20ml) in To a 100 ml 3-necked round bottom flask under nitrogen, n-BuLi in hexane (2.5 M, 2.0 ml, 5.0 mmol) was added dropwise at -70 °C in a liquid nitrogen bath. /EtOH. The resulting solution was stirred for 30 min at -70 °C. Then SO2 was bubbled into the above solution at -70 °C for 30 min. Then, the resulting solution was stirred for 2 h at RT. The reaction solution was concentrated in vacuo. The crude product was dissolved in DCM (15 ml). Then, NCS (199 mg, 1.5 mmol) was added in small portions at RT to the solution.

tion above. The resulting solution was allowed to react, with stirring, for a further 2 h at RT. The resulting mixture was quenched with 15 ml of H2O, the organic layer was collected and washed with 3x15 ml of water, then dried with anhydrous Na2SO4 and concentrated in vacuo. This resulted in 400 mg (crude product) of the title compound as a pale yellow solid. Step 6: N-(tert-butyldimethylsilyl)-4-(1-(tert-butyldimethylsilyloxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002259] To a stirred solution of 4-(1-(tert-butyldimethylsilyloxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide (400 mg, crude product from Step above) in DCM ( 20 ml) in a 100 ml round bottom flask, NH3 (gas) was bubbled through for 10 min at 0 °C. The reaction was stirred for 30 min at RT. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:1) to provide the title compound (1.49 g, 52%, over two steps) as a yellow solid. MS-ESI: 495 (M+1).

[002260] Steps 7 to 8 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 113 from compound 259. MS-ESI: 494 (M+1). Scheme 55:

Intermediate 114 N'-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-methoxypropan-2-yl)thiazol-5-sulfonimidamide

[002261] Step 1 used similar procedures to convert compound 212 to compound 213 shown in Scheme 47 to provide compound 262 from compound 261. MS-ESI: 194/196 (M+1).

[002262] Steps 2 to 3 used similar procedures to convert compound 255 to compound 257 shown in Scheme 54 to provide compound 264 from compound 262. MS-ESI: 288 (M+1). Step 4: 4-((tert-butyldimethylsilyloxy)methyl)-2-(2-methoxypropan-2-yl)thiazol

[002263] To a stirred solution of 2-(4-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)propan-2-ol (2.4 g, 8.3 mmol) in THF (30 ml) in To a 50 ml 3-necked round bottom flask under nitrogen, NaH (60 wt% mineral oil dispersion, 996 mg, 24.9 mmol) was added in portions at 0 °C followed by the addition of iodomethane (3. 55 g, 25 mmol) by dripping at 0 °C in a water/ice bath. The resulting solution was stirred for 16 h at RT. The reaction was quenched with 50 ml of water/ice. The resulting mixture was extracted with 3x100 ml of DCM. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 1.7 g (68%) of the title compound as a yellow solid. MS-ESI: 302 (M+1).

[002264] Steps 5 through 9 used similar procedures to con-

pouring compound 257 into Intermediate 113 shown in Scheme 54 to provide Intermediate 114 from compound 265. MS-ESI: 494 (M+1). Scheme 56: Intermediate 115 N'-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-isopropylthiazol-5-sulfonimidamide Step 1: 4-((tert-butyldimethylsilyloxy)methyl)-2-(prop -1-en-2-yl)thiazole

[002265] To a stirred solution of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (41 g, 244 mmol) in dioxane (420 ml) and water (105 ml) in a 2 L 3-necked round bottom flask under nitrogen were added 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (25 g, 81 mmol), Cs2CO3 (53 g, 162 mmol) and Pd(dppf)Cl2 (5.95 g, 8.1 mmol). The resulting solution was stirred overnight at 80 °C. Solids were removed by filtration. The resulting solution was concentrated in vacuo and diluted with 400 ml of water. The resulting solution was extracted with 3x350 ml of DCM, and the organic layers were combined and dried over anhydrous Na 2 SO 4 . Solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (15:85). This resulted in 18 g (82%) of the title compound as a yellow oil. MS-ESI: 270 (M+1). Step 2: 4-((tert-butyldimethylsilyloxy)methyl)-2-isopropylthiazole

[002266] To a solution of 4-((tert-butyldimethylsilyloxy)methyl)-2-(prop-1-en-2-yl)thiazole (19 g, 71 mmol) in isopropanol (350 ml) in a bottom flask 1 L round under nitrogen, Pd/C (10% by weight, 2.0 g) was added in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen with a balloon. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:9). This resulted in 15 g (78%) of the title compound as a yellow oil. MS-ESI: 272 (M+1).

[002267] Steps 3 to 6 used similar procedures to convert compound 257 to Intermediate 113 shown in Scheme 54 to provide Intermediate 115 from compound 272. MS-ESI: 464 (M+1). Scheme 57:

Intermediate 116 N'-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide Step 1: Ethyl 2-mercaptothiazole-4-carboxylate

[002268] To a stirred solution of ethyl 2-bromothiazole-4-carboxylate (30 g, 127 mmol) in EtOH (200 mL) in a 1 L round bottom flask was added NaSH (36 g, 635 mmol) in portions. The resulting solution was stirred for 3 h at 85 °C under nitrogen. The resulting mixture was concentrated in vacuo. The residue was dissolved in 200 ml of H2O. The pH value of the solution was adjusted to 3 with HCl (1M) below 5°C. The solids were collected by filtration. This resulted in 22 g (91.5%) of the title compound as a yellow solid. MS-ESI: 190 (M+1). Step 2: Ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate

[002269] To a stirred solution of 2-mercaptothiazole-4-carboxylate (16 g, 84.5 mmol) in HCl (6 M, 100 mL) in a 500 mL round bottom flask was added NaClO (10 % by weight, 150 ml, 2.22 mol) by dripping at 0°C. The resulting solution was stirred for 2 h at 0 °C. The reaction mixture was diluted with 500 ml of H2O. The resulting solution was extracted with 3x500 ml of DCM acetate. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. This resulted in 10.8 g of the title compound (crude) as a yellow oil. Step 3: Ethyl 2-sulfamoylthiazole-4-carboxylate

[002270] To a stirred solution of ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate (10.8 g, crude product) in DCM (100 ml) in a 500 ml round bottom flask was bubbled NH3 (g ) for 20 min at 0 °C. The resulting solution was stirred for 1 h at 0 °C. The resulting mixture

was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 18 g (65.5% over two steps) of the title compound as a pale yellow solid. MS-ESI: 237 (M+1). Step 4: 4-(hydroxymethyl)thiazole-2-sulfonamide

[002271] To a stirred solution of ethyl 2-sulfamoylthiazole-4-carboxylate (18 g, 76 mmol) in EtOH (200 mL) in a 500 mL round bottom flask under nitrogen was added NaBH4 (8, 65 g, 229 mmol) in portions at 0 °C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 300 ml of water and extracted with 2x300 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 7.6 g (51.4%) of the title compound as a white solid. MS-ESI: 195 (M+1). Step 5: N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)thiazol-2-sulfonamide

[002272] To a stirred solution of 4-(hydroxymethyl)thiazol-2-sulfonamide (3.1 g, 16 mmol) in THF (25 ml) in a 50 ml round bottom flask under nitrogen was added NaH (60 % by weight of dispersion in mineral oil, 3.06 g, 128 mmol) in several batches at 0 °C in a water/ice bath. The resulting solution was stirred for 10 min at 0 °C. To the above, TBSCl (7.22 g, 47.9 mmol) was added in portions at 0 °C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched with 50 ml of water and extracted with 3x100 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (5:1). This resulted in 3.06 g (45%) of the title compound as a yellow oil. MS-ESI: 423 (M+1). Step 6: N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonamide

[002273] To a stirred solution of N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)thiazol-2-sulfonamide (3.0 g, 7.1 mmol) in THF (20 ml) in a 100 ml 3-necked round bottom flask under nitrogen, n-BuLi in hexane (2.5 M, 4.0 ml, 10 mmol) was added dropwise at -78 °C in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 1 h at -78 °C. This was followed by the addition of propan-2-one (4.12 g, 71 mmol) dropwise at -78 °C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 20 ml of water/ice and extracted with 3x50 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtO-Ac/PE (1:10). This resulted in 1.5 g (44%) of the title compound as a yellow oil. MS-ESI: 481 (M+1).

[002274] Steps 7 to 8 used similar procedures to convert compound 186 to Intermediate 100 shown in Scheme 43 to provide Intermediate 116 from compound 282. MS-ESI: 480 (M+1). Scheme 58: Intermediate 117

N'-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Step 1: 2-(Thiazol-2-yl)propan- 2-hol

[002275] To a stirred solution of 1-(thiazol-2-yl)ethanone (200 g, 1.6 mol) in THF (4 L) in a 10 L 4-necked round bottom flask under nitrogen was added MeMgBr in THF (3M, 942 ml, 2.83 mol) by dripping at 0°C. The resulting solution was stirred for 2 h at 0 °C. The solution was stirred for 16 h at RT. Then, the reaction was quenched by the addition of 3 L of saturated NH4Cl. The resulting solution was extracted with 3x1.0 L of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with an EtO-Ac/PE gradient (1:3 to 1:1). This resulted in 210 g (93%) of the title compound as a brown oil. MS-ESI: 144.0 (M+1). Step 2: Lithium 2-(2-hydroxypropan-2-yl)thiazol-5-sulfinate

[002276] To a stirred solution of 2-(thiazol-2-yl)propan-2-ol (20 g, 140 mmol) in THF (400 mL) in a 1 L 3-necked round bottom flask under nitrogen, n-BuLi in hexane (2.50M, 140 ml, 350 mmol) was added dropwise at -78°C. Then, the resulting solution was stirred for 1 h at -78 °C. Then SO2 (g) was bubbled into the solution at -50 °C for 20 min. The resulting solution was allowed to react, with stirring, for a further 2 h at RT. The resulting mixture was concentrated directly under vacuum. This resulted in 20 g (crude product) of the title compound as a crude yellow solid. MS-ESI: 206 (M-1). Step 3: 2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide

[002277] To a stirred solution of lithium 2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-sulfinate (20 g, crude) in DCM (400 ml) in a round bottom flask of 1 L, NCS (18.8 g, 141 mmol) was added

in portions at 0 °C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with 500 ml of water, then extracted with 3x500 ml of DCM, and the organic layers were combined and dried over anhydrous Na 2 SO 4 . Then, NH3 (g) was bubbled into the DCM mixture for 30 min at 0 °C. The resulting solution was stirred for 2 h at RT and concentrated in vacuo. The residue was eluted from silica gel with EtO-Ac/PE (1/1). This resulted in 2.0 g (6.43% over two steps) of the title compound as a brown solid. MS-ESI: 223 (M+1). Step 4: 2-(Prop-1-en-2-yl)thiazol-5-sulfonamide

[002278] To a stirred solution of 2-(2-hydroxypropan-2-yl)thiazol-5-sulfonamide (50 g, 225 mmol,) in CF3SO3H (60 ml) in a 500 ml round bottom flask was added TFA (60 ml) dripped at RT. The resulting solution was stirred for 16 h at 50 °C in an oil bath. The reaction mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8 with aqueous NaOH (3% by weight). The resulting solution was extracted with 3x300 ml of DCM, and the organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 10 g (21%) of the title compound as an off-white solid. MS-ESI: 205 (M+1). Step 5: 2-(1,2-dihydroxypropan-2-yl)thiazol-5-sulfonamide

[002279] To a stirred solution of 2-(prop-1-en-2-yl)thiazol-5-sulfonamide (10 g, 49 mmol) in t-BuOH (40 ml) and acetone (40 ml) in a flask 250 ml round bottom, NMO (11.5 g, 97.9 mmol) was added, and the resulting solution was stirred for 15 min at RT. Then, a solution of OsO4 (1.24 g, 4.9 mmol) in H2O (60 ml) was added dropwise at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of saturated aqueous Na2S2O3 (50 ml). The resulting solution was extracted with 3x200 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 5.0 g (43%) of the title compound as a yellow oil. MS-ESI: 239 (M+1).

[002280] Steps 6 to 8 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 117 from compound 289. MS-ESI: 466 (M+1). Step 9: (R) and (S) 2-(1,2-dihydroxypropan-2-yl)thiazol-5-sulfonamide

[002281] Compound 289 (5 g) was separated by preparatory chiral HPLC with the following conditions: CHIRALPAK AD, 5*25 cm, 5 µm; Mobile Phase A: CO2, Mobile Phase B: MeOH (2 mM NH3-MeOH); Flow rate: 200 ml/min; Gradient: 40% B; UV 220 nm; Rt1: 3.5 min (Compound 289A); Rt 2 : 5.6 min (Compound 289B). This resulted in 2.0 g (99%ee) of Compound 289A and 2.1 g (98%ee) of Compound 289B, both as white solids. MS-ESI: 237 (M-1). Table 26A. Intermediates 117A and 117B in the Table below were prepared using similar procedures to convert compound 289 to Intermediate 117 shown in Scheme 58 using Compound 289A and Compound 289B. Interme- Exa Mass- Structure IUPAC name daily no. ta [M+H]- (S) or (R) N'-( tert- Interme- N butyldimethylsilyl)-2-(1-( tert- * NH2

daily HO O S S TBS butyldimethylsilyloxy)-2-466

N 117A TBS O hydroxypropan-2-yl)thiazol-5-sulfonimidamide (R) or (S) N'-(tert-Interme-N-butyldimethylsilyl)-2-(1-(tert-*NH 2

daily HO O S S TBS butyldimethylsilyloxy)-2-466

N 117B TBS O-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Scheme 59: Intermediate 118 N'-(tert-butyldimethylsilyl)-5-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-3-fluorothiophene-2-sulfonimidamide Step 1: 5-( methyl chlorosulfonyl)-4-fluorothiophene-2-carboxylate

[002282] To a stirred solution of methyl 4-fluorothiophene-2-carboxylate (10 g, 62.4 mmol) in CHCl3 (100 mL) in a 500 mL round bottom flask was added ClSO3H (21.8 g , 187 mmol) by dripping at 0 °C. The resulting solution was stirred for 12 h at RT. Then, to the above, PCl5 (65 g, 312 mmol) was added at 0 °C in an ice bath. The resulting solution was stirred for 2 h at 50 °C. The reaction solution was poured into 500 ml of water/ice very slowly. The resulting solution was extracted with 3x500 ml of DCM, and the organic layers were combined and dried over anhydrous Na 2 SO 4 . This resulted in a solution of the title compound in DCM (1.5 L) and used for the next step directly without further purification. Step 2: Methyl 4-fluoro-5-sulfamoylthiophene-2-carboxylate

[002283] The DCM solution prepared in the above step was bubbled

of NH3 (gas) at 0 °C for 15 minutes. The reaction solution was stirred for 3 h at RT and concentrated under reduced vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 7.3 g (49% over two steps) of the title compound as a yellow solid. MS-ESI: 240 (M+1). Step 3: 3-Fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[002284] To a stirred solution of methyl 4-fluoro-5-sulfamoylthiophene-2-carboxylate (7.3 g, 30.5 mmol) in THF (200 mL) in a 3-necked round bottom flask of 1 L under nitrogen, MeMgBr in THF (3M, 51 mL, 153 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 14 h at RT and then quenched by the addition of 100 ml of saturated NH4Cl. The resulting solution was extracted with 3x150 ml of EtOAc, and the organic layers were combined, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:1). This resulted in 5.5 g (75%) of the title compound as a white solid. MS-ESI: 240 (M+1).

[002285] Steps 4 to 5 used similar procedures to convert compound 287 to compound 289 shown in Scheme 58 to provide compound 297 from compound 295. MS-ESI: 254 (M-1). Step 6: (R) and (S)-5-(1,2-dihydroxypropan-2-yl)-3-fluorothiophene-2-sulfonamide

[002286] Compound 297 (3.0 g) was separated by preparatory chiral HPLC with the following conditions: Lux® 5µm Amylose-1, 5*25 cm, 5 µm; Mobile Phase A: CO2, Mobile Phase B: MeOH (2 mM NH3); Flow rate: 200 ml/min; Gradient: 50% B; UV 220 nm; Rt1: 3 min (297A); Rt2: 6.8 min (297B); This resulted in 1.1 g of Compound 297A (99% ee) and 1.0 g of Compound 297B (99%ee). MS-ESI: 254 (M-1).

[002287] Steps 7 to 9 used similar procedures to con-

pouring compound 205 into Intermediate 105 shown in Scheme 46 to provide Intermediate 118 from compound 297. MS-ESI: 483 (M+1). Table 26. The Intermediates in the Table below were prepared using the similar procedures to convert compound 297 to Intermediate 118 shown in Scheme 59 using Compound 297A and Compound 297B.

Interme- Exa Mass- Structure IUPAC name daily no. [MH]- (R, RS) or (S, RS) N'-(tert-F TBS butyldimethylsilyl)-5-(1-((tert- Interme- H2N SN butyldimethylsilyl)oxy)-2-daily O 483 HO * S hydroxypropan-2-yl)-3-TBSO fluorothiophene-2-sulfonimidamide (S, RS) or (R, RS) N'-(tert-F TBS butyldimethylsilyl) -5-(1-((tert-Interme-H2 NSN butyldimethylsilyl)oxy)-2-daily O 483 HO * S hydroxypropan-2-yl)-3- 120 TBSO fluorothiophene-2-sulfonimidamide Scheme 60:

Intermediate 121

N'-(tert-butyldimethylsilyl)-3-((tert-butyldimethylsilyloxy)methyl)-1-isopropyl-1H-

pyrazol-4-sulfonimidamide Step 1: 1-Isopropyl-1H-pyrazol-4-sulfonamide

[002288] To a stirred solution of 1-isopropyl-1H-pyrazol-4-sulfonyl chloride (6.0 g, 28.8 mmol) and in DCM (60 ml) in a 250 ml round bottom flask , NH3 (g) was bubbled through at 0 °C for 10 min. The reaction solution was stirred for 1 h at RT and concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 3.2 g (59%) of the title compound as a yellow solid. MS-ESI: 190 (M+1). Step 2: 3-Bromo-1-isopropyl-1H-pyrazol-4-sulfonamide

[002289] To a stirred solution of 1-isopropyl-1H-pyrazol-4-sulfonamide (6.4 g, 33.8 mmol) in THF (100 ml) in a 500 ml 3-necked round bottom flask under nitrogen, n-BuLi in hexane (2.5M, 30 mL, 74.4 mmol) was added dropwise at -78 °C in a liquid nitrogen/EtOH bath. Then, the reaction was stirred for 1 h at -78 °C. To the above mixture, NBS (7.22 g, 40.6 mmol) in THF (20 ml) was added dropwise at -78°C. The resulting mixture was stirred for a further 2 h at RT. The reaction mixture was quenched by the addition of water/ice (50 ml) at 0°C. The resulting mixture was extracted with EtOAc (3x100 ml). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash reverse chromatography with the following conditions: C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2.5 g (28%) of the title compound as a yellow solid. MS-ESI: 268 (M+1). Step 3: Methyl 1-isopropyl-4-sulfamoyl-1H-pyrazole-3-carboxylate

[002290] To a stirred solution of 3-bromo-1-isopropyl-1H-pyrazol-4-sulfonamide (2.0 g, 7.46 mmol) in MeOH (100 mL) in a 250 mL round bottom flask under nitrogen, TEA (3.77 g, 37.3 mmol), Pd(PPh3)4 (862 mg, 0.75 mmol) and Pd(dppf)Cl2 (546 mg, 0.75 mmol) were added. The resulting solution was stirred overnight at 80°C under a CO atmosphere (10 atm). Insoluble matter was removed by filtration, and the filtrate was concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 920 mg (50%) of the title compound as a yellow solid. MS-ESI: 248 (M+1). Step 4: 3-(hydroxymethyl)-1-isopropyl-1H-pyrazol-4-sulfonamide

[002291] To a stirred solution of methyl 1-isopropyl-4-sulfamoyl-1H-pyrazole-3-carboxylate (900 mg, 3.64 mmol) in THF (30 ml) in a 100 ml round bottom flask under nitrogen, BH3 in THF (1 M, 36 mg, 36 mmol) was added dropwise at 0 °C in an ice bath. The reaction solution was stirred overnight at 50 °C. The reaction was quenched with MeOH (30 ml) at 0 °C. The mixture was adjusted to pH 5~6 with HCl (6 M). The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 600 mg (75%) of the title compound as a yellow solid. MS-ESI: 220 (M+1).

[002292] Steps 5 to 6 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 121 from compound 304. MS-ESI: 447 (M+1). Scheme 61: Intermediate 122

N'-(tert-butyldimethylsilyl)-3-(2-hydroxypropan-2-yl)-5-isocyanobenzenesulfonimidamide

[002293] Steps 1 to 2 used similar procedures to convert compound 183 to compound 185 shown in Scheme 43 to provide compound 308 from compound 306. MS-ESI: 241 (M+1).

[002294] Steps 3 to 6 used similar procedures to convert compound 230 to Intermediate 109 shown in Scheme 50 to provide Intermediate 122 from compound 308. MS-ESI: 354 (M+1). Table 27. The Intermediates in the Table below were prepared using similar procedures to convert compound 306 to Intermediate 122 shown in Scheme 61 from suitable starting materials. Interme- Structure Name IUPAC Exact Mass Daily No. [M-H]-N'-(tert-butyldimethylsilyl)-Intermethyl-3-(2-hydroxypropan-2-daily 329yl)benzenesulfonimide 123mide

Scheme 62: Intermediate 124 N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide

[002295] Step 1 used similar procedures to convert compound 300 to compound 301 shown in Scheme 60 to provide compound 313 from compound 312. MS-ESI: 214 (M-1).

[002296] Steps 2 to 5 used similar procedures to convert compound 230 to Intermediate 109 shown in Scheme 50 to provide Intermediate 124 from compound 313. MS-ESI: 329 (M+1). Scheme 63:

Intermediate 125 N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidamide

[002297] Steps 1 to 4 used similar procedures to convert compound 284 to compound 287 shown in Scheme 58 to provide compound 321 from compound 317. MS-ESI: 215 (M+1).

[002298] Steps 5 to 6 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 125 from compound 321. MS-ESI: 330 (M+1). Scheme 64: Intermediate 126 N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)pyridine-2-sulfonimidamide

[002299] Step 1 used similar procedures to convert compound 284 to compound 285 shown in Scheme 58 to provide compound 324 from compound 323. MS-ESI: 215 (M-

1).

[002300] Steps 2 to 4 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 126 from compound 324. MS-ESI: 330 (M+1). Scheme 65: Intermediate 127 The Boc

No

Y N Y NH2

Tert-Butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfanoylidene)carbamate Step 1: 2-(2-Methoxypropan-2-yl)thiazol- 5-methyl sulphinate

[002301] To a stirred solution of methyl 2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-sulfinate (40 g, 181 mmol) in THF (500 ml) in a round bottom flask of 1 L under nitrogen, NaH (60 wt% mineral oil dispersion, 7.95 g, 199 mmol) was added in portions at 0 °C in an ice/ethanol bath. To this reaction solution, MeI (51.3 g, 362 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 ml) at 0 °C. The resulting solution was extracted with 3x300 ml of EtOAc, and the organic layers were combined, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. This resulted in 32 g (75.3%) of the title compound as a white solid. MS-ESI: 236 (M+1).

Step 2: 2-(2-Methoxypropan-2-yl)thiazol-5-sulfinamide

[002302] To a stirred solution of methyl 2-(2-methoxypropan-2-yl)-1,3-thiazol-5-sulfinate (20 g, 85 mmol) in THF (500 ml) in a round bottom flask with 3 1 L bottlenecks under nitrogen, KHMDS in THF (1 M, 1.0 L, 1.0 mol) was added dropwise at -78 °C in a liquid nitrogen/ethanol bath. The resulting solution was stirred for 3 h at -78 °C in a liquid nitrogen/ethanol bath. The reaction was quenched by the addition of water (50 ml). The resulting solution was extracted with 3x300 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 14 g (74.8%) of the title compound as a white solid. MS-ESI: 221.0 (M+1). Step 3: tert-Butyl ((2-(2-methoxypropan-2-yl)thiazol-5-yl)sulfinyl)carbamate

[002303] To a stirred solution of 2-(2-methoxypropan-2-yl)-1,3-thiazol-5-sulfinamide (10 g, 45.4 mmol) in THF (250 ml) in a round bottom flask of 500 ml under nitrogen, NaH (60% by weight of mineral oil dispersion, 3.63 g, 90.8 mmol) was added in portions at 0 °C in an ice/ethanol bath. To this solution, Boc2O (9.91 g, 45.4 mmol) was added in portions at 0 °C in an ice/ethanol bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 ml). The resulting solution was extracted with 3x300 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 12 g (82.5%) of the title compound as a white solid. MS-ESI: 321.1 (M+1). Step 4: tert-Butyl (chloro(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)carbamate

[002304] To a stirred solution of N-[[2-(2-methoxypropan-2-yl)-1,3-

tert-butyl thiazol-5-yl]sulfinyl]carbamate (11 g, 34.3 mmol) in THF (200 ml) in a 500 ml round bottom flask under nitrogen was added NCS (13.8 g, 103 mmol) in small portions at 0 °C. The resulting solution was stirred for 3 h at RT. This reaction was used for the next step directly without further purification. Step 5: tert-Butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfanoylidene)carbamate

[002305] NH3 gas was bubbled into a stirred solution of tert-butyl (chloro(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfanoylidene)carbamate (prepared at from the last step) in THF (200 ml) for 15 min at 0 °C. The resulting solution was stirred for 1 h at RT and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 7.0 g (60.8% over two steps) of the title compound as a white solid. MS-ESI: 336.1 (M+1). Scheme 66: Intermediate 128 N'-(tert-butyldimethylsilyl)-3-chloro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide Step 1: Methyl 4-chlorothiophene-2-carboxylate

[002306] To a stirred solution of 4-chlorothiophene-2-carboxylic acid (9.0 g, 55 mmol) in MeOH (100 ml) in a 100 ml round bottom flask was added H2SO4 (8.0 ml) by dripping at 0 °C in an ice bath. The resulting solution was stirred for 16 h at 70 °C in an oil bath. The reaction solution was poured into 80 ml of water/ice slowly. The pH value of the solution was adjusted to 10 with KOH (sat.). The resulting solution was extracted with 3x80 ml of DCM acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 8.0 g (81.8%) of methyl 4-chlorothiophene-2-carboxylate as a yellow oil. MS-ESI: 177/179 (M+1).

[002307] Steps 2 to 4 used similar procedures to convert compound 292 to compound 295 shown in Scheme 59 to provide compound 336 from compound 333. MS-ESI: 254/256 (M-1).

[002308] Steps 5 to 7 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 128 from compound 336. MS-ESI: 369/371 (M+1). Table 28. The Intermediates in the Table below were prepared using similar procedures to convert compound 332 to Intermediate 128 shown in Scheme 66 from suitable starting materials. Interme- Exa Mass- Structure IUPAC name diary no. [MH]-N'-(tert-Intermebutyldimethylsilyl)-4-chloro-daily 5-(2-hydroxypropan-2- 369/371 129 yl)thiophene-2- sulfonimidamide

Interme- Mass Exa- Structure IUPAC name diary no. [MH]- N-(tert-butyldimethylsilyl)- Intermeth-5-(2-hydroxypropan-2-daily 349yl)-3-methylthiophene-2-sulfonimidamide N'- (tert-Intermebutyldimethylsilyl)-5-(2-daily hydroxypropan-2-yl)-4-methylthiophene-2-sulfonimidamide 3-Bromo-N'-(tert-Intermebutyldimethylsilyl)-5-(2- daily hydroxypropan-2-yl)thiophene-2-sulfonimidamide Scheme 66A:

Intermediate 133

N'-(tert-butyldimethylsilyl)-4-fluoro-5-(2-hydroxypropan-2-yl)thiophene-3-

sulfonimidamide

[002309] Step 1 used similar procedures to convert compound 332 to compound 333 shown in Scheme 66 to provide compound 333A from compound 332A. MS-ESI: 161 (M+1). Step 2: Mixture of methyl 5-(chlorosulfonyl)-3-fluorothiophene-2-carboxylate (Major) and methyl 4-(chlorosulfonyl)-3-fluorothiophene-2-carboxylate (Minor)

[002310] To a stirred solution of methyl 3-fluorothiophene-2-carboxylate (10 g, 62.5 mmol) in CHCl3 (100 mL) in a 500 mL round bottom flask was added ClSO3H (21.8 g , 187 mmol) by dripping at 0 °C. The resulting solution was stirred for 12 h at RT. Then, to the above, PCl5 (65 g, 312 mmol) was added at 0 °C in an ice bath. The resulting solution was stirred for 2 h at 60 °C. The reaction solution was poured into 500 ml of water/ice very slowly. The resulting solution was extracted with 3x500 ml of DCM, and the organic layers were combined and dried over anhydrous Na 2 SO 4 . This resulted in a mixed solution of the title compounds in DCM (1.5 L) and used for the next step directly without further purification. Step 3: Methyl 3-fluoro-5-sulfamoylthiophene-2-carboxylate (Major) and methyl 3-fluoro-4-sulfamoylthiophene-2-carboxylate (Minor)

[002311] To the DCM solution prepared in the last step, NH3 (gas) was bubbled at 0 °C for 15 minutes. The reaction solution was stirred for 3 h at RT, then concentrated under reduced vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 5.4 g (36% over two steps) of methyl 3-fluoro-5-sulfamoylthiophene-2-carboxylate (Compound 335B, main) and 1.8 g (12% over two steps) of 3-fluoro Methyl -4-sulfamoylthiophene-2-carboxylate (Compound 335A,

secondary), both as a yellow solid. MS-ESI: 238 (M-1). Compound 335B: 1H NMR (300 MHz, DMSO-d6) δ 8.07 (s, 2H), 7.63 (s, 1H), 3.86 (s, 3H). F NMR (300 MHz, DMSO-d6) δ -110.93. Compound 335A: 1 H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J = 4.5 Hz, 1H), 7.87 (s1, 2H), 3.85 (s, 3H). 19F NMR (300 MHz, DMSO-d6) δ -113.16.

[002312] Steps 4 to 6 used similar procedures to convert compound 335 to Intermediate 128 shown in Scheme 66 to provide Intermediate 133 from compound 335A. MS-ESI: 353 (M+1). Scheme 67 Intermediate 134

F TBS

N Y NH2

N S O N'-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonimidamide Step 1: (4-Fluorothiophen-2-yl)methanol

[002313] To a stirred solution of methyl 4-fluorothiophene-2-carboxylate (10 g, 62.4 mmol) in ethanol (300 mL) in a 1 L round bottom flask under nitrogen was added NaBH4 (4. 62 g, 125 mmol) in portions at 0 °C in an ice/ethanol bath. The reaction solution was stirred for 16 h at RT. The reaction was then stopped with the addition of 50 ml of water. Then, the mixture was concentrated and extracted with 3x100 ml of EtOAc. The organic layer was combined and dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 6.4 g (77.6%) of the title compound as a yellow oil. MS-ESI: 133 (M+1). Step 2: 2-(Bromomethyl)-4-fluorothiophene

[002314] To a stirred solution of (4-fluorothiophen-2-yl)methanol (8.5g, 64.3mmol) in DCM (70ml) in a 250ml round bottom flask was added PBr3 (19 .2 g, 70.8 mmol) by dripping at 0 °C in an ice/ethanol bath. The resulting solution was stirred for 30 min at 0 °C. The resulting solution was allowed to react for a further 12 h at RT. The reaction was then stopped with the addition of 50 ml of water. Then, the mixture was concentrated and extracted with 3x100 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (15/85). This resulted in 7.0 g (55.8%) of the title compound as a yellow oil. MS-ESI: 194/196 (M+1). Step 3: 1-(4-Fluorothiophen-2-yl)-N,N-dimethylmethanamine

[002315] To a stirred solution of 2-(bromomethyl)-4-fluorothiophene (7.4 g, 37.9 mmol) in CHCl 3 (50 mL) in a 250 mL round bottom flask was added butoxytributyl sulfate. λ4-azane (6.76 g, 19 mmol) and DMA (37 ml, 425 mmol) at RT. The resulting solution was stirred for 2 h at 60 °C. The reaction was then quenched by the addition of 50 ml of water. Then, the organic solvent was removed, and the residue was extracted with 3x100 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (17/83). This resulted in 5.1 g (85%) of the title compound as a yellow solid. MS-ESI: 160 (M+1).

[002316] Steps 4 to 9 used similar procedures to con-

pouring compound 257 into Intermediate 113 shown in Scheme 54 to provide Intermediate 134 from compound 342. MS-ESI: 352 (M+1).

[002317] Schemes for Amino Pyridine Intermediates: Schemes 68 to 83 illustrate the preparation of amino pyridine intermediates. Scheme 68: Intermediate 135 Ethyl 4-amino-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate Step 1: 4-amino-3-methyl-6,7-di ethyl -hydro-5H-cyclopenta[b]pyridine-2-carboxylate

[002318] To a stirred solution of 2-aminocyclopent-1-ene-1-carbonitrile (20 g, 185 mmol) in DCE (400 ml) in a 1 L round bottom flask under nitrogen was added 2-oxobutanoate of ethyl (24.1g, 185mmol) and BF3.Et2O (47% by weight, 25g, 370mmol) dripped at 0°C. The resulting solution was stirred for 4 h at 80 °C in an oil bath. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 500 ml of water. The pH value of the solution was adjusted to 8 with K2CO3 (sat.). The resulting solution was

extracted with 3x500 ml of EtOAc.

The organic layers were dried over anhydrous Na2SO4.

The resulting mixture was concentrated in vacuo.

The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 900 mg (2.2%) of the title compound as a yellow solid.

MS-ESI: 221 (M+1). Table 29. The Intermediates in the Table below were prepared using similar procedures to convert compound 348 to Intermediate 135 shown in Scheme 68 from suitable starting materials.

Interme- Exact Mass Structure Daily IUPAC Name No. [M-H]-

2-(2,2,2-Trifluoroethyl)-Interme-6,7-dihydro-5H-daily 217 cyclopenta[b]pyridin-4-amine

3-Methyl-2-Interme-(trifluoromethyl)-6,7-di-daily hydro-5H- cyclopenta[b]pyridin-4-amine

2-Isopropyl-3-methyl-6,7-Intermedihydro-5H-daily 191 cyclopenta[b]pyridin-4-amine

2-Cyclopropyl-3-methyl-Interme-6,7-dihydro-5H-daily 203 cyclopenta[b]pyridin-4-amine

Interme- Exact Mass Structure IUPAC Name Daily No. [MH]- Interme- 3-Ethyl-1,2,3,5,6,7-hexa-daily hydrodicyclopent-203 140 ta[b,e]pyridin-8-amine 2 ,4,5,6-tetrahydro-1H-Intermecyclobutyric 161 ta[b]cyclopenta[e]pyridin 141 -7-amine Scheme 69: Intermediate 142 2-Isopropyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-3-amine Step 1: 3-Nitro-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one

[002319] To a stirred solution of 1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (5.0 g, 37 mmol) in DCM/conc. (10:1) (55 ml) in a 250 ml round bottom flask, KNO3 (4.11 g, 40.7 mmol) was added in portions at 0 °C in an ice bath. The resulting solution was stirred for 4 h at RT. The resulting solution was poured into 200 ml of ice/water. The mixture was extracted with 3x200 ml of DCM. The organic layer was dried with anhydrous Na2SO4 and concentrated

under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 621 mg (9.3%) of the title compound as a yellow solid. MS-ESI: 181 (M+1). Step 2: 2-Chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine

[002320] To a stirred solution of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (621 mg, 3.4 mmol) in MeCN (30 ml) to a 100 ml round bottom flask, POCl 3 (2.61 g, 17 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 6 h at 60 °C and concentrated in vacuo. The mixture was dissolved in DCM. Then, the solution was poured into 10 ml of water/ice and extracted with 3x30 ml of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtO-Ac/PE (1:5). This resulted in 417 mg (61%) of the title compound as a yellow solid. MS-ESI: 199 (M+1). Step 3: 3-Nitro-2-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

[002321] To a stirred solution of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (410 mg, 2.1 mmol) in 1,4-dioxane/H 2 O (5 :1) (24 ml) in a 100 ml round bottom flask under nitrogen was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3, 2-dioxaborolane (521 mg, 3.1 mmol), K3PO4 (890 mg, 4.2 mmol) and Pd(dtbpf)Cl2 (135 mg, 0.21 mmol). The resulting solution was stirred for 6 h at 60 °C. The reaction mixture was diluted with 20 ml of H2O and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 235 mg (55.7%) of the title compound as a brown solid. MS-ESI: 205 (M+1). Step 4: 2-Isopropyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine

[002322] To a stirred solution of 3-nitro-2-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (235 mg, 1.15 mmol) in MeOH (10 ml)

in a 50 ml round bottom flask under nitrogen, Pd/C (10% by weight, 24 mg) was added. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred for 2 h at RT under a hydrogen atmosphere with a balloon. Solids were removed by filtration. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 197 mg (97%) of the title compound as a white solid. MS-ESI: 177 (M+1). Scheme 70: Intermediate 143 3-Ethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002323] Step 1 used similar procedures to convert compound 348 to intermediate 135 shown in Scheme 68 to provide compound 354 from compound 353. MS-ESI: 203 (M+1). Step 2: 3-Bromo-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002324] To a stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1.5g, 7.42mmol) in MeCN (200ml) in a 500 ml round bottom flask under nitrogen, NBS (10.6 g, 59.4 mmol) was added. The resulting solution was stirred overnight at RT. The reaction was then stopped with the addition of 50 ml of saturated Na2S2O3 (aq). The mixture was extracted with 3x100 ml of EtOAc. The organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1/3). This resulted in 1.1 g (53%) of the title compound as a dark yellow solid. MS-ESI: 281/283 (M+1).

[002325] Steps 3 to 4 used similar procedures to convert compound 351 to Intermediate 142 shown in Scheme 69 to provide Intermediate 143 from compound 355. MS-ESI: 231 (M+1). Scheme 71: Intermediate 144 5-Amino-4,6-diisopropylpicolinonitrile

[002326] Step 1 used similar procedures to convert compound 354 to compound 355 shown in Scheme 70 to provide compound 358 from compound 357. MS-ESI: 276/278 (M+1).

Step 2: 5-Amino-4,6-di(prop-1-en-2-yl)picolinonitrile

[002327] To a stirred solution of 5-amino-4,6-dibromopicolinonitrile (3.3 g, 12 mmol) in dioxane (125 ml) and H2O (17 ml) in a 500 ml round bottom flask under nitrogen, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.0 g, 29.8 mmol), Cs2CO3 (11.7 g, 35.8 mmol) and Pd(dppf)Cl 2 (1.74 g, 2.4 mmol). The resulting solution was stirred overnight at 90 °C in an oil bath. The resulting solution was concentrated under vacuum. The reaction solution was diluted with 200 ml of H2O. The mixture was extracted with 3x200 ml of EtOAc, and the organic layers were dried with anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 1.96 g (82.5%) of the title compound as a yellow oil. MS-ESI: 200 (M+1).

[002328] Step 3 used similar procedures to convert compound 352 to Intermediate 142 shown in Scheme 69 to provide Intermediate 144 from compound 359. MS-ESI: 204 (M+1). Scheme 72:

Intermediate 145 2,6-Dicyclopropyl-3,5-dimethylpyridin-4-amine Step 1: 2,6-Dibromo-3,5-dimethylpyridine 1-oxide

[002329] To a stirred solution of 2,6-dibromo-3,5-dimethylpyridine (2.0 g, 7.55 mmol) in TFA (20 ml) in a 100 ml round bottom flask was added H2O2 ( 30% by weight, 4.0 ml) by dripping at 0°C. The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting solution was diluted with 100 ml of water. The mixture was extracted with 3x100 ml of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 1.5 g (71%) of the title compound as a brown solid. MS-ESI: 280/282/284 (M+1). Step 2: 2,6-Dibromo-3,5-dimethyl-4-nitropyridine 1-oxide

[002330] To a stirred solution of 2,6-dibromo-3,5-dimethylpyridine 1-oxide (1.50 g, 5.34 mmol) in conc. (20 ml) in a 100 ml round bottom flask, HNO3 (4.0 ml) was added dropwise at 0 °C in an ice bath. The resulting solution was stirred for 4 h at 60 °C in an oil bath. The reaction was poured into 100 ml of water/ice slowly. The resulting solution was extracted with 3x100 ml of DCM acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 1.3 g (74.7%) of the title compound as a brown solid. MS-ESI: 325/327/329 (M+1). Step 3: 2,6-Dibromo-3,5-dimethylpyridin-4-amine

[002331] To a stirred solution of 2,6-dibromo-3,5-dimethyl-4-nitropyridine 1-oxide (1.3 g, 3.99 mmol) in AcOH (20 mL) in a vial of 100 ml round bottom under nitrogen Fe powder was added

(1.11 g, 0.020 mmol). The resulting mixture was stirred for 14 h at 35 °C. Insoluble matter was removed by filtration, and the filtrate was diluted with 50 ml of water. The resulting solution was extracted with 3x50 ml of DCM acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtO-Ac/PE (1:10 to 1:3). This resulted in 900 mg (80.6%) of the title compound as a brown solid. MS-ESI: 278/280/282 (M+1).

[002332] Step 4 used similar procedures to convert compound 358 to Intermediate 359 shown in Scheme 71 to provide Intermediate 145 from compound 363. MS-ESI: 203 (M+1). Scheme 73: Intermediate 146 3,7-Dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 2-Methylhexanedinitrile

[002333] To a stirred solution of LDA (76.4 ml, 153 mmol) in 200 ml of THF in a 1 L 3-necked round bottom flask under nitrogen was added a cold solution of adiponitrile (15 g, 139 mmol) in THF (50 ml) by dripping at -78 °C in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 1 h at -78 °C. To the reaction, CH 3 I (21.7 g, 153 mmol) in THF (50 ml) was added dropwise at -78 °C. Then, the reaction was stirred for 1 h at -10 °C. The reaction was quenched with saturated NH4Cl (100 ml). The THF was removed, and the mixture was extracted with 3x200 ml of EtOAc, and the organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. This resulted in 15 g of the title compound (crude) as a yellow oil. MS-ESI: 123 (M+1). Step 2: 2-Amino-3-methylcyclopent-1-ene-1-carbonitrile

[002334] To a stirred solution of 2-methylhexanenitrile (15 g, 123 mmol) in THF (450 mL) in a 1 L 3-necked round bottom flask under nitrogen was added NaH (60% in mineral oil dispersion weight, 9.84 g, 246 mmol) in portions at 0 °C in an ice/EtOH bath. The reaction was stirred for 30 min at 0 °C and then overnight at 80 °C. The reaction was quenched with 200 ml of H2O. The mixture was extracted with 3x300 ml of EtOAc. The combined organic layer was dried over anhydrous Na2SO4. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 4.8 g (28% over two steps) of the title compound as a yellow solid. MS-ESI: 123 (M+1).

[002335] Step 3 used similar procedures to convert compound 348 to Intermediate 135 shown in Scheme 68 to provide Intermediate 146 from compound 366. MS-ESI: 231 (M+1).

Scheme 74: Intermediate 147 2-Cyclopropyl-3,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 2-Cyclopropyl-7-methyl-6,7-di -hydro-5H-cyclopenta[b]pyridin-4-amine

[002336] To a stirred solution of 2-amino-3-methylcyclopent-1-ene-1-carbonitrile (25.4 g, 208 mmol) in toluene (150 ml) in a 500 ml round bottom flask under nitrogen, 1-cyclopropylethan-1-one (35 g, 416 mmol) and ZnCl 2 (31 g, 229 mmol) were added in portions. The resulting solution was stirred for 16 h at 110 °C in an oil bath. The reaction was then stopped with the addition of 200 ml of water. The pH value of the solution was adjusted to 14 with NaOH (3M). The resulting solution was extracted with 3x300 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:5). The crude product was further purified by prep. with the following conditions: Column XBridge Prep C18 OBD 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 17% B to 18% B over 10 min; 254/210 nm; Rt: 9.30 min. This resulted in 1.5 g (3.8%) of the title compound as a pale yellow oil. MS-ESI: 189 (M+1).

[002337] Step 2 used similar procedures to convert compound 354 to compound 355 shown in Scheme 70 to provide compound 368 from compound 367. MS-ESI: 267/269 (M+1). Step 3: 2-cyclopropyl-3,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002338] To a stirred solution of 3-bromo-2-cyclopropyl-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1.5 g, 5.61 mmol) in dioxane (25 mL) and H2O (2.5 mL) in a 100 mL round bottom flask under nitrogen, Cs2CO3 (4.57 g, 14 mmol), Pd(dppf)Cl2.CH2Cl2 (0.46 g, 0.56 mmol) and 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (1.99 g, 14 mmol). The resulting solution was stirred for 16 h at 90 °C in an oil bath. The reaction was then quenched by the addition of 50 ml of water. The resulting solution was extracted with 3x50 ml of DCM, and the organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 0.60 g (53%) of the title compound as a pale yellow oil. MS-ESI: 203 (M+1). Table 30. The Intermediates in the Table below were prepared using similar procedures to convert compound 366 to Intermediate 147 shown in Scheme 74 from suitable starting materials.

Interme-Exact Mass [M- Structure IUPAC Name Daily No. H]-3-Cyclopropyl-2-methyl-Interme-6,7-dihydro-5H-Daily 189 cyclopenta[b]pyridin-148 4-amine Scheme 75: Intermediate 149 2-(tert-Butyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002339] Step 1 used similar procedures to convert compound 348 to Intermediate 135 shown in Scheme 68 to provide compound 369 from compound 348. MS-ESI: 191 (M+1).

[002340] Step 2 used similar procedures to convert compound 354 to compound 355 shown in Scheme 70 to provide compound 370 from compound 369. MS-ESI: 269/271 (M+1). Step 3: 2-(tert-butyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-

4-amine

[002341] To a stirred solution of 3-bromo-2-(tert-butyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (550 mg, 2.04 mmol) in a 100 ml round bottom flask under nitrogen, Cs2CO3 (1.33 g, 4.09 mmol), 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (435 mg, 3, 06 mmol), Pd(dppf)Cl 2 (145 mg, 0.20 mmol) and SPhos (84 mg, 0.20 mmol). The resulting solution was stirred overnight at 80 °C. The reaction solution was diluted with 20 ml of H2O. The resulting mixture was extracted with 3x50 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (50:1). This resulted in 243 mg (58%) of the title compound as a brown solid. MS-ESI: 205 (M+1). Table 31. The Intermediates in the Table below were prepared using similar procedures to convert compound 348 to Intermediate 149 shown in Scheme 75 from suitable starting materials. Interme- Mass Exa- Structure IUPAC Name diary no. [MH]-2,3-Dicyclopropyl-6,7-di-Intermehydro-5H-daily 215 cyclopenta[b]pyridin-4-150 amine 2-(Difluoromethyl) -3-methyl-Interme-6,7-dihydro-5H-daily 199 cyclopenta[b]pyridin-4-amine 2-cyclopropyl-3-isopropyl-Interme-6,7-dihydro-5H-daily 217 cyclopenta[b]pyridin-4-152 amine Scheme 76:

Intermediate 153 2-(Cyclopropylmethyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Intermediate 154 3-Cyclopropyl-2-ethyl-6,7-dihydro-5H -cyclopenta[b]pyridin-4-amine Step 1: 2-Cyclopropylacetyl chloride

[002342] To a stirred solution of 2-cyclopropylacetic acid (10 g, 99.9 mmol) in DCM (200 ml) in a 500 ml round bottom flask under nitrogen was added oxalyl chloride (14 g, 110 mmol ) by dripping at 0 °C in an ice bath. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated in vacuo. This resulted in 10 g (crude product) of the title compound as a colorless oil. Step 2: 2-Cyclopropyl-N-methoxy-N-methylacetamide

[002343] To a stirred solution of 2-cyclopropylacetyl chloride (10 g, crude product) in DCM (200 ml) in a round-bottomed flask of

500 ml, TEA (25.7 g, 254 mmol) was added, followed by the addition of N,O-dimethylhydroxylamine hydrochloride (16.4 g, 169 mmol) in DCM (50 ml) dropwise at 0 °C in an ice bath. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 200 ml of water. The mixture was extracted with 3x200 ml of DCM, and the organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. This resulted in 22 g (91%) of the title compound as a colorless oil. MS-ESI: 144 (M+1). Step 3: 1-Cyclopropylbutan-2-one

[002344] To a stirred solution of 2-cyclopropyl-N-methoxy-N-methylacetamide (20 g, 140 mmol) in THF (200 mL) in a 500 mL round bottom flask under nitrogen was added EtMgBr in Et2O ( 2M, 91 ml, 182 mmol) by dripping at 0 °C in an ice bath. The resulting solution was stirred for 14 h at RT. The reaction was then quenched by the addition of 200 ml of water. The mixture was extracted with 3x200 ml of DCM, and the organic layers were dried with anhydrous Na2SO4 and concentrated in vacuo. This resulted in 13 g (83%) of the title compound as a brown liquid. MS-ESI: 113 (M+1). Step 4: 2-(Cyclopropylmethyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine and 3-Cyclopropyl-2-ethyl-6,7-dihydro-5H - cyclopenta[b]pyridin-4-amine

[002345] To a stirred solution of 1-cyclopropylbutan-2-one (9.64 g, 89.1 mmol) in DCE (100 ml) in a 250 ml round bottom flask under nitrogen was added 1-cyclopropylbutan-2- 2-one (10 g, 89 mmol) and BF3.Et2O (47 wt.%, 19 g, 134 mmol) dripped at 0 °C in an ice bath. The resulting solution was stirred for 14 h at 80 °C in an oil bath. The resulting solution was diluted with 100 ml of water. The pH value of the solution was adjusted to 9 with NaOH (3M). The resulting solution was extracted with 3x300 ml of DCM acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (100:1 to 10:1) and resulted in a mixture. Then, the mixture was separated by SFC with the following conditions: Ultimate XB-NH2, 21.2*250 mm; 5 um; Mobile Phase A: CO2, Mobile Phase B: EtOH (8 mM NH3.MeOH); Flow rate: 60 ml/min; Gradient: 35% B for 9 min; UV 220 nm; Rt1: 6.25 min Intermediate 153; Rt2: 7.40 min Intermediate 154; Injection volume: 1.1 ml; Number of rounds:100; this resulted in Intermediate 153 (4.0 g) and Intermediate 154 (2.0 g). MS-ESI: 203 (M+1). Scheme 77: Intermediate 155 3-Methyl-2-(1-methylcyclopropyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002346] Steps 1 to 4 used similar procedures to convert compound 371 to Intermediate 153 shown in Scheme 76 to provide Intermediate 155 from compound 375. MS-ESI: 203 (M+1).

Scheme 78: Intermediate 156 3-Methoxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine Step 1: 8-chloro-1,2,3,5,6 ,7-hexahydrodicyclopenta[b,e]pyridine

[002347] To a stirred solution of 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (1.75 g, 10 mmol) in CHCl 3 (80 mL) in a 500 ml round bottom flask under nitrogen, tert-butyl nitrite (2.06 g, 20 mmol) and CuCl 2 (2.70 g, 20 mmol) were added portionwise at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was washed with 3x50 ml of water and dried over anhydrous Na 2 SO 4 . The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (10:1). This resulted in 1.1 g (57%) of the title compound as a yellow oil. MS-ESI: 194/196 (M+1). Step 2: 8-Chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide

[002348] To a stirred solution of 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine (1.10 g, 5.7 mmol) in CHCl 3 (60 ml) to a 250 ml round bottom flask, m-CPBA (1.96 g, 11.4 mmol) was added in portions at 0 °C. The resulting mixture was stirred for 3 h at RT. The reaction was quenched with saturated Na2SO3 at 0

°C. The resulting mixture was washed with 3x15 ml of water and dried over anhydrous Na2SO4. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 1.03 g (86.5%) of the title compound as a yellow oil. MS-ESI: 210/212 (M+1). Step 3: 8-Chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl acetate

[002349] A solution of 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide (1.0 g, 4.8 mmol) in Ac2O (50 ml ) in a 100 ml round bottom flask was stirred overnight at RT. The resulting mixture was concentrated under reduced pressure. This resulted in 550 mg (crude product) of the title compound as a yellow oil. MS-ESI: 252/254 (M+1). Step 4: 8-Chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol

[002350] To a stirred solution of 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl acetate (550 mg, crude) in MeOH (25 ml) and H2O (5 ml) in a 100 ml round bottom flask, NaOH (224 mg, 5.6 mmol) was added in portions at 0 °C. The reaction solution was stirred for 6 h at 60 °C. The mixture was cooled to RT and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 550 mg (55% over two steps) of the title compound as a colorless oil. MS-ESI: 210/212 (M+1). Step 5: 8-Chloro-3-methoxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine

[002351] To a stirred solution of 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol (550 mg, 2.6 mmol) in THF (25 ml) in a 100 ml 3-necked round bottom flask under nitrogen, NaH (60% by weight dispersion in mineral oil, 208 mg, 5.2 mmol) was added in portions at 0 °C in an ice bath. The resulting mixture was stirred for 30 min at 0 °C. To the above solution, CH3I (745 mg, 5.2 mmol) was added at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. The reaction was quenched with water/ice (5 ml) at 0°C. The mixture was extracted with 3x15 ml of EtOAc. The organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (10:1). This resulted in 500 mg (85%) of the title compound as a yellow oil. MS-ESI: 224/226 (M+1). Step 6: 3-Methoxy-N-(4-methoxybenzyl)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

[002352] To a stirred solution of 8-chloro-3-methoxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine (500 mg, 2.2 mmol) in 1.4 -dioxane (15 ml) and H2O (1 ml) in a 100 ml round bottom flask under nitrogen were added (4-methoxyphenyl)methanamine (613 mg, 4.4 mmol) and Cs2CO3 (1.45 g, 4 .4 mmol) and Pd2(dba)3 (20.5 mg, 0.022 mmol) and X-Phos (21.31 mg, 0.045 mmol). The resulting solution was stirred overnight at 100°C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with H 2 O (10 ml) and extracted with 3x15 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 370 mg (51%) of the title compound as a yellow solid. MS-ESI: 325 (M+1). Step 7: 3-Methoxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

[002353] The solution of 3-methoxy-N-(4-methoxybenzyl)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (370 mg, 1.14 mmol) in TFA (10 ml) was stirred for 3 h at 80 °C. The resulting mixture was concentrated in vacuo. This resulted in 450 mg (crude product) of the title compound as a yellow solid. MS-ESI: 205 (M+1).

Scheme 79: Intermediate 157 Ethyl 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine-3-carboxylate Step 1: 8-amino-1,2,3,5 ethyl ,6,7-hexahydrodicyclopenta[b,e]pyridine-3-carboxylate

[002354] To a stirred solution of P2O5 (27.3 g, 192 mmol) in toluene (100 ml) in a 250 ml round bottom flask under nitrogen was added triethyl phosphate (22.5 g , 123 mmol) by drip at 55~60 °C, followed by the addition of ethanol (2.20 g, 9.55 mmol) by drip at 55~60 °C. The reaction was stirred for 30 min. The solution was cooled to RT, the mixture of 2-aminocyclopent-1-ene-1-carbonitrile (3.81 g, 35 mmol) and ethyl 2-oxocyclopentane-1-carboxylate (5.0 g , 32 mmol) in toluene (20 ml) at RT. Then, the solution was stirred for 3.5 h at 55 °C. The solution was cooled to RT, water (100 ml) was added dropwise below 40 °C in an ice bath. Then, the solution was stirred at 55 °C for 30 min. The aqueous phase was collected and the pH value adjusted to 8 with saturated Na2CO3 solution. The resulting solution was extracted with 3x150 ml of EtOAc, the combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (17:1).

This resulted in 1.1 g (15%) of the title compound as a brown solid. MS-ESI: 247 (M+1). Intermediate 158 3-(Fluoromethyl)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine Step 2: (8-Amino-1,2,3,5,6 ,7-hexahydrodicyclopenta[b,e]pyridin-3-yl)methanol

[002355] To a stirred solution of ethyl 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine-3-carboxylate (680 mg, 2.76 mmol) in THF (10 ml) in a 50 ml round bottom flask under nitrogen, LiBH4 (180 mg, 8.28 mmol) was added portionwise at 0 °C in an ice bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 5 ml of water. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (8:1). This resulted in 220 mg (39%) of the title compound as an off-white solid. MS-ESI: 205 (M+1). Step 3: 3-(Fluoromethyl)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

[002356] To a stirred solution of (8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl)methanol (50 mg, 0.25 mmol) in DCM (10 ml) in a 50 ml 3-necked round bottom flask under nitrogen, DAST (197 mg, 1.22 mmol) was added dropwise at 0 °C in an ice bath. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 ml of MeOH. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). The crude product was purified by prep HPLC. under the following conditions: Column XBridge Prep OBD C18 30×150 mm 5 µm; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 25% B to 42% B in 7 min; 254/210 nm; Rt: 6.83 min. This resulted in 75 mg (99%) of the title compound as a pale yellow oil. MS-ESI: 247 (M+1). Scheme 80: Intermediate 159 1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridin-5-amine Step 1: 2,3,4,6,7,8-hexahydrodicyclopenta[b ,d]pyridin-5(1H)-one

[002357] To a stirred solution of 2-oxocyclopentane-1-carboxamide (2.0 g, 15.7 mmol) in toluene (80 ml) in a 250 ml 3-necked round bottom flask under nitrogen were added cyclopentanone (1.32 g, 15.7 mmol) and TsOH (1.63 g, 9.44 mmol) were added. The resulting solution was stirred for 4 h at 120 °C in an oil bath. The mixture was concentrated under reduced pressure. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 301 mg (11%) of the title compound as a yellow solid. MS-ESI: 176 (M+1).

Step 2: 5-Chloro-1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridine

[002358] A stirred solution of 2,3,4,6,7,8-hexahydrodicyclopenta[b,d]pyridin-5(1H)-one (301 mg, 1.72 mmol) in phosphoryl trichloride (25 ml) in a 100 ml round bottom flask was stirred for 16 h at 150 °C in an oil bath. The reaction was then quenched by the addition of H2O (200 ml). The pH value of the solution was adjusted to 7 with NaOH (3M). The resulting solution was extracted with 3x150 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by prep HPLC. under the following conditions: Column XBridge Prep C18 OBD 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 35% B to 80% B in 8 min; 254/210 nm; Rt: 7.00 min. This resulted in 152 mg (46%) of the title compound as a white solid. MS-ESI: 194/196 (M+1). Step 3: N-(4-methoxybenzyl)-1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridin-5-amine

[002359] To a stirred solution of 5-chloro-1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridine (156 mg, 0.81 mmol) in dioxane (25 ml) in a 100 ml 3-necked round bottom flask under nitrogen, 1-(4-methoxyphenyl)methanamine (221 mg, 1.62 mmol), t-BuOK (272 mg, 2.43 mmol), Pd2( dba)3 (74 mg, 0.081 mmol) and Davephos (32 mg, 0.081 mmol). The resulting solution was stirred for 4 h at 100 °C in an oil bath. The reaction mixture was diluted with H2O (20 ml) and extracted with 3x50 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 168 mg (71%) of the title compound as a yellow oil. MS-ESI: 295 (M+1). Step 4: 1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridin-5-amine

[002360] To a stirred solution of N-(4-methoxybenzyl)-1,2,3,6,7,8-

hexahydrodicyclopenta[b,d]pyridin-5-amine (100 mg, 0.34 mmol) in CHCl 3 (5 mL) in a 50 mL round bottom flask, TFA (5 mL) was added dropwise at 0° Ç. The resulting solution was stirred for 2 h at 65 °C in an oil bath. The solution was concentrated under vacuum. The residue was dissolved in DCM (10 ml). The pH value of the solution was adjusted to 10 with NaOH (3M). The resulting mixture was extracted with 3x20 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 50 mg (84%) of the title compound as a white solid. MS-ESI: 175 (M+1). Scheme 81: Intermediate 160 Phenyl (4-Cyclopropyl-6-methylpyrimidin-2-yl)carbamate Step 1: 4-Cyclopropyl-6-methylpyrimidin-2-amine

[002361] To a stirred solution of 1-cyclopropylbutane-1,3-dione (2.0 g, 16 mmol) in DMF (20 ml) in a 100 ml sealed tube was added K2CO3 (4.42 g , 32 mmol) and guanidine hydrochloride (3.02 g, 32 mmol). The resulting solution was stirred for 4 h at 150 °C in an oil bath. The resulting mixture was concentrated in vacuo. The mixture was dissolved in 20 ml of EtOAc. The resulting mixture was washed with 2x50 ml of H2O. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 1.6 g (68%) of the title compound as a yellow solid. MS-ESI: 150 (M+1). Step 2: Phenyl (4-Cyclopropyl-6-methylpyrimidin-2-yl)carbamate

[002362] To a stirred solution of 4-cyclopropyl-6-methylpyrimidin-2-amine (100 mg, 0.67 mmol) in THF (20 ml) in a 50 ml round bottom flask under nitrogen was added NaH ( 60% by weight dispersion in mineral oil, 53.6 mg, 1.34 mmol) and phenyl chloroformate (115 mg, 0.74 mmol). The resulting solution was stirred for 24 h at RT. The reaction solution was quenched with H2O (10 ml). The mixture was extracted with 3x20 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 150 mg (83%) of the title compound as a white solid. MS-ESI: 270 (M+1). Scheme 82: Intermediate 161 (R)-3-Methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine Step 1: (R)-3-Methyl-1 ,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

[002363] A stirred solution of 3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (47 g, 250 mmol) in isopropyl alcohol (423 ml) was heated to 80 °C in a 1 L 3-neck flask with condenser and stir bar. The solution was stirred for 0.5 h. The solution was cooled to about 50 °C. The solution was filtered at this temperature through a Buchner funnel to

move insoluble impurities.

The solid was washed with isopropyl alcohol (3x10ml). The filtrate was transferred to a round bottle and concentrated to 350 g.

The solution was transferred to a 2 L 3-necked round bottom flask equipped with a mechanical stirrer and reflux condenser in an oil bath.

The round bottle was washed with 27 g of isopropyl alcohol to transfer all material into the 2 L 3-neck bottle.

The resulting solution was heated to 80°C, and a solution of (R)-(-)-Mandelic acid (38 g, 250 mmol) in isopropyl alcohol (188 ml) was added dropwise at that temperature.

The resulting mixture was stirred at 80 °C for 5 min.

The system was cooled in a step of 5 °C and a small amount of the product seed crystals was added.

If the seed has dissolved, repeat the above operation.

When the system was cooled to 65 °C, the seed was undissolved and crystals started to grow, the system slowly became cloudy, the solution was stirred for 30 minutes at this temperature.

Thereafter, the solution was stirred and held for 30 minutes while the temperature was cooled in 5 °C steps until the system temperature was 40 °C.

Turn off the oil bath heating switch, and the mixture is slowly cooled to 28 °C.

After 16 h, the ee value of the solid was monitored (96%ee). The solid was collected by filtration.

The resulting solid was slurried in isopropyl alcohol (180 ml) for 1 h and filtered again.

The filtrate was decanted, and the precipitate was washed with chromatographic isopropyl alcohol (30 ml) to give the title compound as a white solid (35 g, 40.5% yield, 98%ee, which contains 13.8% IPA ). The solid was dissolved in water (420 ml) and concentrated to provide 29.2 g of white solid (KF=5.1%). The mother liquor was combined and concentrated to provide 56.7 g of S-isomer (75%ee, contains 17.8% IPA) as a foam.

Then 26.9 g of salt (R) was released by aqueous Na2CO3 (4M, 500 ml) and extracted with 3x300 ml of EA, then the organic phase was washed with 500 ml of brine and dried with anhydrous Na2SO4 and concentrated under vacuum. This resulted in 14.3 g (38% yield, 98%ee, LCAP=96%) of the title compound as a white solid. MS-ESI: 189 (M+1). Chiral analysis method: Column, CHIRALPAK IC 4.6*150 mm, 3 μm. Mobile phase: Hex(0.1% DEA):IPA=85:15. Column Temperature: 30°C. Flow Rate: 1.0 ml/min. Monitor: UV 254 nm. Intermediate 161 is the first peak with a retention time of 5.8 min. The S enantiomer is the second peak with a retention time of 7.0 min.

[002364] In a separate experiment, crystals were obtained from Intermediate 45 and (S)-(+)-Mandelic acid using similar procedures. The structure of this salt was separated by single crystal X-ray crystallography to be the (S) enantiomer of Intermediate 45. Therefore, Intermediate 161 has the (R) configuration. Scheme 83: Intermediate 162 Ethyl 3-methyl-4-(((2,2,2-trichloroethoxy)carbonyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate Step 1 : 3-methyl-4-(((2,2,2-trichloroethoxy)carbonyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate

[002365] To a stirred solution of ethyl 4-amino-3-methyl-5H,6H,7H-cyclopenta[b]pyridine-2-carboxylate (500 mg, 2.27 mmol) in THF (30 ml) in a 100 mL round bottom flask under nitrogen, DIEA (587 mg, 4.54 mmol) was added at RT, followed by the addition of 2,2,2-trichloroethyl chloroformate (962 mg, 4.54 mmol) dropwise. to RT.

The resulting solution was stirred overnight at RT.

The reaction solution was quenched with H2O (10 ml). The mixture was extracted with 3x50 ml of EtOAc.

The organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo.

The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 610 mg (68%) of the title compound as a yellow-brown solid.

MS-ESI: 395/397/399 (M+1). Table 32. The Intermediates in the following Table were prepared using similar procedures to convert Intermediate 135 to Intermediate 162 shown in Scheme 83 from suitable starting materials.

Interme- Exact Mass Structure IUPAC name daily no. [MH]-(2-(2,2,2-trifluoroethyl)- Interme-6,7-dihydro-5H-daily cyclopenta[b]pyridin-4-391/393 /395 163 2,2,2-Trichloroethyl (3-Methyl-2-(trifluoromethyl)-6,7-di-Intermehydro-5H-daily)carbamate 391/393/395 cyclopenta[b]pyridin-4 - 164 2,2,2-trichloroethyl yl)carbamate

Interme- Exact Mass Structure IUPAC Name Daily No. [MH]-(2-Isopropyl-3-methyl-Interme-6,7-dihydro-5H-Daily cyclopenta[b]pyridin-4-365/367/369 165 yl 2,2,2-Trichloroethyl (2-cyclobutyl-3-methyl-Intermeth-6,7-dihydro-5H-daily cyclopenta[b]pyridin-4-377/379/381 166 yl)carbamate of 2,2,2-Trichloroethyl (3-ethyl-1,2,3,5,6,7-hexa-Intermehydrodicyclopendicum 377/379/281 ta[b,e]pyridin-8-167yl)carbamate 2,2,2-Trichloroethyl (2,4,5,6-tetrahydro-1H-Intermecyclobudanium ta[b]cyclopenta[e]pyridin 335/337/339 168 -7-yl)carbamate of 2,2,2-Trichloroethyl (2,2,2,2-Trichloroethyl 2-isopropyl-6,7-di-Intermehydro-5H-daily cyclopenta[b]pyridin-3-351/353/355 169yl)carbamate 2,2,2-Trichloroethyl (3-ethyl-2-(trifluoromethyl)-Intermeth-6,7-dihydro-5H-daily cyclopenta[b]pyridin-4-405/407/409 170yl)carbamate

Interme- Exact Mass Structure IUPAC Name Daily No. [MH]-(3,7-Dimethyl-2-(trifluoromethyl)-6,7-di-Intermehydro-5H-Daily 405/407/409 cyclopenta[b]pyridin- 4-171 2,2,2-trichloroethyl yl)carbamate

2,2,2-Trichloroethyl (2,6-dicyclopropyl-3,5-Intermedimethylpyridin-4-daily 377/379/381)carbamate

2,2,2-173 Trichloroethyl (6-cyano-2,4-di-Intermeisopropylpyridin-3-daily 378/380/382yl)carbamate

2,2,2-Trichloroethyl (2-cyclopropyl-3,7-Intermedimethyl-6,7-dihydro-5H-daily cyclopenta[b]pyridin-4-377/379/381 174yl)carbamate ( 2,2,2-Trichloroethyl (2-( tert-butyl)-3-methyl-Intermeth-6,7-dihydro-5H-daily cyclopenta[b]pyridin-4-379/381/383 176 2,2,2-trichloroethyl yl)carbamate

Exact Mass Intermediate Structure IUPAC Name Daily No. [MH]-(2,3-Dicyclopropyl-6,7-Intermedi-Dihydro-5H-Daily Cyclopenta[b]pyridin-4-389/391/393 177 yl)carbamate of 2,2,2-trichloroethyl

2,2,2-Trichloroethyl (2-(difluoromethyl)-3-Intermethyl-6,7-dihydro-5H-daily cyclopenta[b]pyridin-4-373/375/377 178yl)carbamate

2,2,2-Trichloroethyl (2-(cyclopropylmethyl)-3-Intermethyl-6,7-dihydro-5H-daily cyclopenta[b]pyridin-4-377/379/381 179yl)carbamate

2,2,2-Trichloroethyl (3-cyclopropyl-2-ethyl-6,7-Intermedihydro-5H-daily cyclopenta[b]pyridin-4-377/379/381 180yl)carbamate

2,2,2-(3-methyl-2-(1-methylcyclopropyl)-6,7-di-Intermehydro-5H-daily 377/379/381 cyclopenta[b]pyridin-4-181yl)carbamate trichloroethyl (3-methoxy-1,2,3,5,6,7-hexa-Intermehydrodicyclopendiary 379/381/383 ta[b,e]pyridin-8-182yl)carbamate of 2,2,2 - trichloroethyl

Interme- Exact Mass Structure IUPAC Name Daily No. [MH]- 8-(((2,2,2-Trichloroetho- Intermexi)carbonyl)amino)- Daily 1,2,3,5,6,7-hexa- 421/423/425 183 ethyl hydrodicyclopenta[b,e]pyridine-3-carboxylate

2,2,2-Trichloroethyl (1,2,3,6,7,8-hexa-intermehydrodicyclopendiary ta[b,d]pyridin-5-349/351/353 184yl)carbamate

(R)-(3-Methyl-1,2,3,5,6,7-hexa-Intermehydrodicyclopendial 363/365/367 ta[b,e]pyridin-8-185yl)carbamate of 2, 2,2-Trichloroethyl (2-cyclopropyl-3-Intermeisopropyl-6,7-dihydrodaily 5H-cyclopenta[b]pyridin-391/393/395 186 4-yl)carbamate -trichloroethyl (3-(fluoromethyl)-1,2,3,5,6,7-hexa-Intermehydrodicyclopendial 381/383/385 ta[b,e]pyridin-8-187yl)carbamate of 2, 2,2-trichloroethyl Scheme 84:

Intermediate 188 N'-(tert-butyldimethylsilyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazol-5-sulfonimidamide Step 1: 2,2-Dimethyl-5- (thiazol-2-yl)-1,3-dioxan-5-ol

[002366] To a stirred solution of 2-bromothiazole (4.89 g, 30.0 mmol) in THF (200 ml) in a 500 ml 3-necked round bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 12.0 ml, 30 mmol) by dripping at -70 °C in a liquid nitrogen/ethanol. The resulting solution was stirred for 1 h at -70 °C. Then, 2,2-dimethyl-1,3-dioxan-5-one (3.9 g, 30 mmol) in THF (10 ml) was added dropwise at -70 °C. The resulting solution was stirred for a further 30 min at RT. The reaction solution was quenched with H2O (200 ml). The resulting mixture was extracted with EtOAc (3x200ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1/10). This resulted in 3.2 g (50%) of the title compound as a yellow solid. MS-ESI: 216 (M+1).

[002367] Steps 2 to 5 used similar procedures to convert compound 257 to Intermediate 113 shown in Scheme 54 to provide Intermediate 188 from compound 394. MS-ESI: 408 (M+1).

Scheme 85: Intermediate 189 N'-(tert-butyldimethylsilyl)-1-(1,1-difluoroethyl)-1H-pyrazol-3-sulfonimidamide Step 1: 1-(2-Bromo-1,1-difluoroethyl)-3- nitro-1H-pyrazole

[002368] To a stirred solution of 2-bromo-1,1-difluoroethene (8.5 g, 59 mmol) in MeCN (30 ml) in a 100 ml round bottom flask under nitrogen was added 3-nitro- 1H-pyrazole (6.7 g, 59 mmol) in small portions at -30 °C followed by the addition of DBU (18.1 g, 119 mmol) dropwise at -30 °C. The resulting solution was stirred for 4 h at -20 °C. The resulting solution was concentrated in vacuo. The resulting mixture was diluted with water (100 ml). The resulting mixture was extracted with 3x100 ml of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 4.2 g (28%) of the title compound as a yellow oil. MS-ESI: 256/258 (M+1). Step 2: 1-(2-Bromo-1,1-difluoroethyl)-1H-pyrazol-3-amine

[002369] To a stirred solution of 1-(2-bromo-1,1-difluoroethyl)-3-nitro-1H-pyrazole (2.0 g, 7.81 mmol) in MeOH (20 mL) in a flask of 100 ml round bottom under nitrogen, Pd(OH) 2 /C (20% by weight, 395 mg) was added in portions at RT. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred for 2 days at RT under a hydrogen atmosphere with a balloon. Solids were removed by filtration. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 200 mg (11%) of the title compound as a brown oil. MS-ESI: 226/228 (M+1).

[002370] Steps 3 to 4 used similar procedures to convert compound 183 to compound 185 shown in Scheme 43 to provide compound 402 from compound 400. MS-ESI: 290/292 (M+1). Step 5: 1-(1,1-Difluoroethyl)-1H-pyrazol-3-sulfonamide

[002371] To a stirred solution of 1-(2-bromo-1,1-difluoroethyl)-1H-pyrazol-3-sulfonamide (1.0 g, 3.45 mmol) in MeOH (40 ml) in a reaction To a 100 ml pressure tank under nitrogen, Pd(OH) 2 /C (20% by weight, 200 mg) was added in portions at 0°C. The resulting solution was stirred for 24 h at 70 °C under a hydrogen atmosphere (10 atm). Solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtO-Ac/PE (1:1). This resulted in 620 mg (85%) of the title compound as a white solid. MS-ESI: 210 (M-1).

[002372] Steps 6 to 7 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 189 from compound 403. MS-ESI: 325 (M+1).

Scheme 86: Intermediate 190 N'-(tert-butyldimethylsilyl)-4-ethylthiophene-2-sulfonimidamide

[002373] Steps 1 to 6 used similar procedures to convert compound 257 to Intermediate 133 shown in Scheme 54 to provide Intermediate 190 from compound 405. MS-ESI: 305 (M+1). Scheme 87: Intermediate 191

N'-(tert-butyldimethylsilyl)-5-ethyl-3-fluorothiophene-2-sulfonimidamide Step 1: 4-Fluorothiophene-2-carboxylic acid

[002374] To a stirred solution of methyl 4-fluorothiophene-2-carboxylate (300 mg, 1.87 mmol) in MeOH (10 ml) in a 50 ml round bottom flask was added a solution of NaOH (300 mg, 7.49 mmol) in H 2 O (10 ml) by dropping at 0 °C. The resulting solution was stirred for 2 h at RT. The pH value of the solution was adjusted to 4 with HCl (6M). The resulting solution was extracted with 3x20 ml of EtOAc and dried over anhydrous Na 2 SO 4 and concentrated in vacuo. This resulted in 200 mg (73%) of the title compound as a white solid. MS-ESI: 145 (M-1). Step 2: 4-Fluoro-N-methoxy-N-methylthiophene-2-carboxamide

[002375] To a stirred solution of 4-fluorothiophene-2-carboxylic acid (200 mg, 1.37 mmol) in THF (15 ml) in a 50 ml round bottom flask under nitrogen was added TEA (346 mg, 3.42 mmol) and N,O-dimethylhydroxylamine hydrochloride (202 mg, 2.06 mmol) at RT. To the stirred solution, T3P in EtOAc (50% by weight, 1.74 g, 2.74 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 4 h at RT. The reaction solution was quenched with 20 ml of water. The resulting solution was extracted with 3x20 ml of EtOAc, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 200 mg (77%) of the title compound as a yellow oil. MS-ESI: 190 (M+1). Step 3: 1-(4-Fluorothiophen-2-yl)ethan-1-one

[002376] To a stirred solution of 4-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (200 mg, 1.06 mmol) in THF (10 ml) in a 50 ml 3-necked round bottom flask under nitrogen, MeMgBr in THF (3.0 M, 0.53 ml, 1.59 mmol) was added dropwise with stirring at 0 °C in 5 min. The resulting solution was stirred for 1 h at

RT. The reaction was then quenched by the addition of 5.0 ml of NH4Cl (aq). The resulting solution was extracted with 3x10 ml of DCM acetate. The combined extract was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 120 mg (79%) of the title compound as a yellow oil. MS-ESI: 145 (M+1). Step 4: 2-(4-Fluorothiophen-2-yl)-2-methyl-1,3-dioxolane

[002377] To a stirred solution of 1-(4-fluorothiophen-2-yl)ethan-1-one (120 mg, 0.83 mmol) in toluene (10 ml) in a 100 ml round bottom flask , ethane-1,2-diol (103 mg, 1.66 mmol) and 4-methylbenzenesulfonic acid (14 mg, 0.083 mmol) were added. The resulting solution was stirred for 16 h at 110 °C. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtO-Ac/PE (1:3). This resulted in 121 mg (77%) of the title compound as a yellow oil. MS-ESI: 189 (M+1).

[002378] Steps 5 to 6 used similar procedures to convert compound 257 to compound 259 shown in Scheme 54 to provide compound 417 from compound 415. MS-ESI: 268 (M+1). Step 7: 5-Acetyl-3-fluorothiophene-2-sulfonamide

[002379] To a stirred solution of 3-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)thiophene-2-sulfonamide (360 mg, 1.35 mmol) in THF (10 ml) in to a 50 ml round bottom flask, HCl (4 M, 10 ml, 40 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 3 h at 60 °C in an oil bath. The resulting mixture was concentrated in vacuo. The pH value of the solution was adjusted to 8 with saturated Na2CO3. The resulting mixture was extracted with EtOAc (3x30ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 300 mg (99%) of the title compound as a yellow oil. MS-ESI: 224 (M+1).

Step 8: 5-Ethyl-3-fluorothiophene-2-sulfonamide

[002380] To a stirred solution of 5-acetyl-3-fluorothiophene-2-sulfonamide (300 mg, 1.34 mmol) in TFA (1.53 g, 13.4 mmol) in a 50 ml round bottom flask under nitrogen, triethylsilane (1.56 g, 13.4 mmol) was added dropwise at RT. The resulting solution was stirred for 16 h at 30 °C in an oil bath. The resulting mixture was concentrated in vacuo. The pH value of the solution was adjusted to 8 with Na2CO3. The resulting mixture was extracted with EtOAc (3x30ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 240 mg (85%) of the title compound as a yellow oil. MS-ESI: 210 (M+1).

[002381] Steps 9 to 11 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 191 from compound 419. MS-ESI: 323 (M+1). Scheme 88: Intermediate 192

N-(tert-butyldimethylsilyl)-2-((R)-2-hydroxy-1-(2-methoxyethoxy)propan-2-yl)thiazol-5-sulfonimidamide Step 1: (R)-2-4-methylbenzenesulfonate hydroxy-2-(5-sulfamoylthiazol-2-yl)propyl

[002382] To a stirred solution of (R)-2-(1,2-dihydroxypropan-2-yl)thiazol-5-sulfonamide (Compound 289A, 4.0 g, 17 mmol) in pyridine (40 ml) to a 250 ml round bottom flask under nitrogen, 4-methylbenzenesulfonyl chloride (4.8 g, 25 mmol) was added in portions at 0 °C. The resulting solution was stirred overnight at RT and then diluted with HCl (1M, 40 ml) and extracted with 3x40 ml of EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 5.2 g (79%) of the title compound as a yellow solid. MS-ESI: 391 (M-1). Step 2: (R)-2-(2-hydroxy-1-(2-methoxyethoxy)propan-2-yl)thiazol-5-sulfonamide

[002383] To a stirred solution of 2-methoxyethan-1-ol (1.94 g, 25 mmol) in THF (30 ml) in a 100 ml round bottom flask under nitrogen was added NaH (60% by weight dispersion in mineral oil, 2.04 g, 51 mmol) in portions at 0°C. The resulting mixture was stirred for 30 min at 0°C. To the solution, (R)-2-hydroxy-2-(5-sulfamoylthiazol-2-yl)propyl 4-methylbenzenesulfonate (2.0 g, 5. 1 mmol) in portions at 0 °C. The resulting mixture was stirred for 32 h at 35 °C. The reaction solution was quenched with water (20 ml) to 0°C. The resulting mixture was extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine (2x200 ml) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:3). This resulted in 1.18 g (78%) of the title compound as a yellow oil. MS-ESI: 295 (M+1).

[002384] Steps 3 to 5 used similar procedures to convert compound 205 to Intermediate 105 shown in Scheme 46 to provide Intermediate 192 from compound 423. MS-ESI: 410 (M+1). Scheme 89: Intermediate 193 N-(tert-butyldimethylsilyl)-3-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-N-methylbenzenesulfonamide Step 1: N1,N3-bis(tert-butyldimethylsilyl)-N1-methylbenzene-1, 3- disulfonamide

[002385] To a stirred solution of N-methylbenzene-1,3-disulfonamide (220 mg, 0.88 mmol) in THF (6.0 mL) in a 25 mL round bottom flask under nitrogen was added NaH ( 60% by weight mineral oil dispersion, 211 mg, 5.28 mmol) in portions at 0°C. The resulting solution was stirred for 20 min at RT. To the solution, TBSCl (397 mg, 2.64 mmol) was added in portions at 0 °C. The resulting solution was stirred overnight at RT. The reaction solution was quenched with 10 ml of water. The mixture was extracted with 3x20 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 400 mg (95%) of the title compound as a yellow oil. MS-ESI: 479 (M+1).

[002386] Steps 2 to 4 used similar procedures to convert compound 186 to Intermediate 100 shown in Scheme 43 to provide Intermediate 193 from compound 427. MS-ESI: 478 (M+1). Scheme 90: Intermediate 194 N'-(tert-butyldimethylsilyl)-4-chloro-1-ethyl-1H-pyrazol-3-sulfonimidamide Step 1: 1-ethyl-3-nitro-1H-pyrazole

[002387] To a stirred solution of 3-nitro-1H-pyrazole (30 g, 265 mmol) in DMF (150 ml) in a 500 ml round bottom flask was added K2CO3 (73.3 g, 530 mmol) in portions at RT. Iodoethane (82.8 g, 530 mmol) was added dropwise at RT. The resulting solution was stirred for 1 h at 80 °C. The reaction was then quenched by the addition of 500 ml of water. The resulting mixture was extracted with 4x200 ml of EtOAc and dried over anhydrous Na 2 SO 4 . Solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 36 g (96%) of the title compound as a yellow oil.

MS-ESI: 142 (M+1). Step 2: 1-ethyl-1H-pyrazol-3-amine

[002388] To a stirred solution of 1-ethyl-3-nitro-1H-pyrazole (10 g, 71 mmol) in MeOH (100 ml) in a 250 ml round bottom flask under nitrogen was added Pd/C ( 10% by weight, 1.13 g) in portions at 0°C. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred for 16 h at RT under hydrogen using a balloon. Solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (15:1). This resulted in 5.7 g (72%) of the title compound as a yellow oil. MS-ESI: 112 (M+1).

[002389] Steps 3 to 5 used similar procedures to convert compound 218 to compound 221 shown in Scheme 48 to provide compound 434 from compound 431. MS-ESI: 290 (M+1). Step 6: N-(tert-butyldimethylsilyl)-4-chloro-1-ethyl-1H-pyrazol-3-sulfonamide

[002390] To a stirred solution of N-(tert-butyldimethylsilyl)-1-ethyl-1H-pyrazol-3-sulfonamide (100mg, 0.35mmol) in DMF (10ml) in a 25 ml under nitrogen, NCS (50.7 mg, 0.38 mmol) was added in portions at 0 °C. The resulting solution was stirred overnight at RT. The reaction solution was diluted with 10 ml of H2O. The resulting mixture was extracted with 3x20 ml of EtOAc, the combined organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 80 mg (71.5%) of the title compound as a yellow solid. MS-ESI: 324/326 (M+1).

[002391] Steps 7 through 8 used similar procedures to convert compound 186 to Intermediate 100 shown in the Scheme

43 to provide Intermediate 194 from compound 435. MS-ESI: 323 (M+1).

[002392] Schemes of Sulfonimidamide Intermediates: Schemes 91 to 106 illustrate the preparation of sulfonimidamide intermediates. Scheme 91: Intermediate 195 N'-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-3-sulfonimidamide Step 1: 1-(2-(benzyloxy)ethyl) -3-nitro-1H-pyrazole

[002393] To a stirred solution of 3-nitro-1H-pyrazole (10 g, 88 mmol) in DMF (120 ml) in a 500 ml 3-necked round bottom flask was added K2CO3 (18 g, 133 mmol) and ((2-bromoethoxy)methyl)benzene (20 g, 93 mmol) portionwise at RT. The resulting solution was stirred for 16 h at 60 °C in an oil bath. The reaction was then stopped with the addition of 150 ml of water. The resulting solution was extracted with 3x200 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with EtO-Ac/PE (1:3). This resulted in 21.1 g (96.7%) of the title compound as a yellow oil. MS-ESI: 248 (M+1). Step 2: 1-(2-(Benzyloxy)ethyl)-1H-pyrazol-3-amine

[002394] To a stirred solution of 1-(2-(benzyloxy)ethyl)-3-nitro-1H-pyrazole (20 g, 81 mmol) in THF (200 ml) and AcOH (50 ml) in a bottom flask 1 L round under nitrogen, Fe powder (45 g, 810 mmol) was added. The resulting mixture was stirred for 4 h at RT. The solids were removed by filtration, to the filtrate was added 400 ml of water. The resulting solution was extracted with 3x300 ml of EtOAc, the organic layers were combined and dried over anhydrous Na 2 SO 4 . The residue was eluted from silica gel with EtOAc/PE (3:1). This resulted in 14.8 g (84%) of the title compound as a pink oil. MS-ESI: 218 (M+1). Step 3: 1-(2-(Benzyloxy)ethyl)-1H-pyrazol-3-sulfonyl chloride

[002395] To a stirred solution of 1-(2-(benzyloxy)ethyl)-1H-pyrazol-3-amine (10 g, 46 mmol) in MeCN (100 ml) in a 500 ml round bottom flask , HBF4 (aq., 40% by weight, 15 g, 69.1 mmol) was added at RT, followed by the addition of tert-butyl nitrite (7.12 g, 69 mmol) dropwise below 5 °C in an ice/water bath. The resulting solution was stirred for 1.5 h at 0~5 °C, this solution designated solution A. Then, CuCl (13.7 g, 138 mmol) was added to a round-bottomed flask with a 500 ml neck. with MeCN (200 ml) as the solvent. Then SO2 (g) was bubbled into the solution with stirring at RT for 20 min, this solution was designated solution B. To solution B, solution A was added dropwise with stirring at 0 °C. The resulting solution was stirred for a further 3 h at RT. The reaction was then stopped with the addition of 500 ml of water. The resulting solution was extracted with 3x300 ml of EtOAc. The organic layers were combined and washed with 3x300 ml of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 12.8 g (crude product) of the title compound as a yellow-brown oil. MS-ESI: 301 (M+1). Step 4: 1-(2-(Benzyloxy)ethyl)-1H-pyrazol-3-sulfonamide

[002396] A solution of 1-(2-(benzyloxy)ethyl)-1H-pyrazol-3-sulfonyl chloride (crude product from last step, 12.8g) in MeOH/NH3 (7M, 300ml) in a 500 ml round bottom flask was stirred for 16 h at RT. The resulting solution was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (20:1). This resulted in 5.4 g (42% over two steps) of the title compound as a yellow-brown oil. MS-ESI: 282 (M+1). Step 5: 1-(2-hydroxyethyl)-1H-pyrazol-3-sulfonamide

[002397] To a stirred solution of 1-(2-(benzyloxy)ethyl)-1H-pyrazol-3-sulfonamide (5.4 g, 19.2 mmol) in MeCN (100 mL) in a round-bottomed flask of 250 ml under nitrogen, KI (6.37 g, 38 mmol) was added in portions at RT. To the stirred solution, BF3.Et2O (47% by weight, 13 g, 192 mmol) was added dropwise at RT. The resulting solution was stirred for 4 h at RT. The reaction was then stopped with the addition of 5.0 ml of water. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (15:1). This resulted in 4.6 g (93%) of the title compound as a yellow solid. MS-ESI: 192 (M+1). Step 6: N-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-3-sulfonamide

[002398] To a stirred solution of 1-(2-hydroxyethyl)-1H-pyrazol-3-sulfonamide (4.1 g, 21 mmol) in THF (60 ml) in a 250 ml round bottom flask under nitrogen, NaH (60 wt% mineral oil dispersion, 3.86 g, 96.5 mmol) was added at 0 °C in a water/ice bath. The resulting mixture was stirred for 20 min at RT. To the stirred mixture, TBSCl (13.6 g, 90 mmol) was added at 0 °C. The resulting mixture was stirred for 5 h at RT. The reaction was then stopped with the addition of 300 ml of water. The resulting mixture was extracted with 3x150 ml of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 6.2 g (69%) of the title compound as an off-white solid. MS-ESI: 420 (M+1). Step 7: N'-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-3-sulfonimidamide

[002399] To a stirred solution of PPh3Cl2 (1.51 g, 3.57 mmol) in CHCl3 (15 mL) in a 50 mL 3-necked round bottom flask under nitrogen was added DIEA (924 mg, 7, 15 mmol) by dripping at 0 °C. The resulting solution was stirred for 20 min at 0 °C. To the stirred solution, N-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-3-sulfonamide (600 mg, 1.43 mmol) in CHCl 3 (5 .0 ml) by dripping at 0°C. The resulting solution was stirred for 2 h at 0 °C. NH3(g) was bubbled into the reaction solution for 15 min at 0 °C. Then, the solution was stirred for a further 2 h at RT. The reaction was then stopped with the addition of 20 ml of H2O. The resulting solution was extracted with 3x20 ml of DCM acetate. The organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 320 mg (53%) of the title compound as a yellow solid. MS-ESI: 419 (M+1). Scheme 92:

Intermediate 196 N'-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazol-3-sulfonimidamide Step 1 : Methyl 1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-pyrazole-5-carboxylate

[002400] To a stirred solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (5.0 g, 29 mmol) in MeCN (50 mL) in a 250 mL round bottom flask was added Cs2CO3 ( 19 g, 58 mmol) at RT. To the stirred solution, ethyl 2-bromoacetate (5.36 g, 35 mmol) was added dropwise at RT. The resulting solution was stirred for 0.5 h at 50 °C. The mixture was diluted with 100 ml of H2O. The resulting solution was extracted with 3x50 ml of EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 3.8 g (50%) of the title compound as a yellow oil. MS-ESI: 258 (M+1). Step 2: Methyl 3-amino-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate

[002401] To a stirred solution of methyl 1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-pyrazole-5-carboxylate (1.4 g, 5.43 mmol) in MeOH (30 ml) in a 250 ml round bottom flask, Pd/C (10% by weight, 300 mg) was added under nitrogen in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen with a balloon. The solid was filtered off. The resulting solution was concentrated in vacuo. This resulted in 1.18 g (95%) of the title compound as a white solid. MS-ESI: 228 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 6.94 (sl, 2H), 6.29 (s, 1H), 5.11 (s, 2H), 4.14 (q, J = 7.1 Hz , 2H), 3.79 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). The structure of compound 446 was confirmed by NOESY. Step 3: Methyl 3-(chlorosulfonyl)-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate

[002402] To a stirred solution of methyl 3-amino-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate (1.18 g, 5.17 mmol) in HCl (6 M, 30 ml) in a 100 ml 3-necked round bottom flask, NaNO2 (1.07 g, 15.5 mmol) in H2O (1.0 ml) was added dropwise at -10 °C. The resulting mixture was stirred for 1 h at -10 °C, this solution was designated solution A. Then, CuCl2 (348 mg, 2.59 mmol) was added to a round bottom flask with a 250 ml neck with AcOH (30 ml) as the solvent, SO 2 (g) was bubbled into the solution with stirring at RT for 20 min, that solution was designated B. To solution B, solution A was added dropwise with stirring at -10°C. The resulting solution was stirred for a further 1 h at 0 °C. The resulting mixture was extracted with DCM (3 x 30 ml). The combined organic layers were washed with water (3x30ml) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under vacuum. This resulted in 1.7 g (crude product) of the title compound as a yellow solid. Step 4: Methyl 1-(2-ethoxy-2-oxoethyl)-3-sulfamoyl-1H-pyrazole-5-carboxylate

[002403] To a solution of methyl 3-(chlorosulfonyl)-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate (1.7 g, crude product) in DCM (50 ml) in a 250 ml round bottom flask, NH3 (g) was introduced and bubbled for 15 min at 0 °C. The reaction was stirred for 2 h at RT. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 1.33 g (88%) of the title compound as a yellow solid. MS-ESI: 290 (M-1).

Step 5: 1-(2-hydroxyethyl)-5-(hydroxymethyl)-1H-pyrazol-3-sulfonamide

[002404] To a stirred solution of methyl 1-(2-ethoxy-2-oxoethyl)-3-sulfamoyl-1H-pyrazole-5-carboxylate (1.33 g, 4.55 mmol) in EtOH (30 ml) to a 100 ml round bottom flask, NaBH4 (865 mg, 22.8 mmol) was added in portions at 0 °C. The mixture was stirred overnight at RT. The reaction was quenched by the addition of saturated NH4Cl (aq.) (20 ml) at 0°C. The EtOH solvent was removed under vacuum. The resulting mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with H2O (3x20ml) and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 889 mg (88%) of the title compound as a pale yellow solid. MS-ESI: 222 (M+1).

[002405] Steps 6 to 7 used similar procedures to convert compound 442 to Intermediate 195 shown in Scheme 91 to provide Intermediate 196 from compound 449. MS-ESI: 564 (M+1). Scheme 93: Intermediate 197

N-(tert-butyldimethylsilyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide Step 1: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[002406] To a stirred solution of 4-fluoro-1H-pyrazole (5.0 g, 58 mmol) in DMF (53 mL) in a 250 mL 3-necked round bottom flask under nitrogen was added NaH (60% by weight dispersion in mineral oil, 5.36 g, 134 mmol) in portions at 0 °C in an ice/water bath for 10 min. The resulting solution was stirred for 30 min at 10 °C. Thereto, SEM-Cl (22 g, 134 mmol) was added dropwise with stirring at 0 °C for 10 min. The resulting solution was stirred overnight at RT. The reaction was then quenched with 60 ml of water. The resulting solution was extracted with 60 ml of EtOAc. The combined organic layer was washed with 5x60 ml of saturated NaCl solution. The resulting mixture was concentrated. The residue was eluted from a silica gel column with EtO-Ac/PE (1:100). This resulted in 13.7 g (crude product) of the title compound as a pale yellow liquid. MS-ESI: 217 (M+1). Step 2: Lithium 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-sulfinate

[002407] To a stirred solution of 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (13.7 g, 63 mmol) in THF (150 ml) in a round bottom flask with 3 500 ml bottlenecks under nitrogen, n-BuLi in hexane (2.5 M, 28 ml, 70 mmol) was added by dropping at -78 °C in a liquid nitrogen/EtOH over 15 min. The resulting solution was stirred for 1 h at -78 °C. Then, to the mixture, was introduced SO2 (g) bubbled for 20 min -78 °C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. This resulted in 20.4 g (crude product) of the title compound as a white solid. Step 3: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-sulfonyl chloride

[002408] To a stirred solution of lithium 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-sulfinate (20.4 g, crude) in DCM (396 ml) and H2O (198 mL) in a 1 L 3-necked round bottom flask, NCS (10 g, 78 mmol) was added in portions at 0 °C. The resulting solution was stirred for 1 h at 10 °C. The raw product was used directly without finishing. Step 4: N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-sulfonamide

[002409] To the stirred solution of 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-sulfonyl chloride in DCM (396 ml) and H 2 O (198 ml) from the last step, Et3N (8.85 g, 87 mmol) and dibenzylamine (17 g, 84 mmol) were added dropwise at 0 °C. The resulting solution was stirred for 1 h at 8 °C. The reaction was then quenched by the addition of 300 ml of water. The resulting solution was extracted with 3x300 ml of DCM acetate. The organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:19). This resulted in 22.5 g (81% over four steps) of the title compound as a pale yellow oil. MS-ESI: 476 (M+1). Step 5: N,N-dibenzyl-4-fluoro-1-(hydroxymethyl)-1H-pyrazol-5-sulfonamide

[002410] To a stirred solution of N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-sulfonamide (22.5 g, 47 mmol) in DCM (25 ml) in a 250 ml round bottom flask, TFA (25 ml) was added. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 15 g (85%) of the title compound as a yellow oil. MS-ESI: 376 (M+1). Step 6: N,N-dibenzyl-4-fluoro-1H-pyrazol-5-sulfonamide

[002411] To a stirred solution of N,N-dibenzyl-4-fluoro-1-

(hydroxymethyl)-1H-pyrazol-5-sulfonamide (15g, 40mmol) in dioxane (50ml) in a 500ml round bottom flask, NH3.H2O (30% by weight, 50ml) was added dropwise. at 0 °C in an ice/water bath. The resulting solution was stirred for 3 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 12 g (87%) of the title compound as a white solid. MS-ESI: 346 (M+1). Step 7: N,N-Dibenzyl-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonamide and N,N-dibenzyl-1-ethyl-4-fluoro-1H-pyrazol-5-sulfonamide

[002412] To a stirred solution of N,N-dibenzyl-4-fluoro-1H-pyrazol-5-sulfonamide (1.1 g, 3.2 mmol) in DMF (20 ml) in a round bottom flask with 3 100 ml bottlenecks under nitrogen, K2CO3 (0.88 g, 6.4 mmol) was added in portions at RT and ethyl iodide (0.99 g, 6.4 mmol) was added dropwise at RT. The resulting solution was stirred for 3 h at 110 °C. The reaction was then quenched by the addition of 20 ml of water. The resulting solution was extracted with 2x20 ml of EtO-Ac. The organic layers were dried with anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (3:17). This resulted in 764 mg (64%) of 458A and 218 mg (18%) of 458B, both as a pale yellow solid. MS-ESI: 374 (M+1). Step 8: 1-Ethyl-4-fluoro-1H-pyrazol-3-sulfonamide

[002413] To a stirred solution of N,N-dibenzyl-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonamide (764 mg, 2.0 mmol) in DCM (1.5 ml) in a vial of 25 ml round bottom, H2SO4 (98% by weight, 3.00 ml) was added dropwise at 0 °C in an ice/water bath. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 5.0 ml of water/ice. The mixture was extracted with EtOAc (3x50 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with DCM/MeOH (93:7). This resulted in 317 mg (80%) of the title compound as a white solid. MS-ESI: 194 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J = 4.7 Hz, 1H), 7.77 (s, 2H), 4.14 (q, J = 7.3 Hz, 2H ), 1.39 (t, J = 7.3 Hz, 3H). The structure of compound 459 was confirmed by NOESY.

[002414] Steps 9 to 10 used similar procedures to convert compound 442 to Intermediate 195 shown in Scheme 91 to provide Intermediate 197 from compound 459. MS-ESI: 307 (M+1) Table 44. Intermediates in the following table were prepared using similar procedures to convert compound 451 to Intermediate 197 shown in Scheme 93. Interme- Exa Mass- Structure IUPAC Name Daily Ta No. [MH]-

TBS O NH N-(tert-butyldimethylsilyl)-Interme-S 1-(difluoromethyl)-4-daily N NH 329 F fluoro-1H-pyrazol-3-198 N F sulfonimidamide

F Scheme 94: Intermediate 199F N'-(tert-butyldimethylsilyl)-4-((S)-1-((tert-butyldimethylsilyl)oxy)-2-

hydroxypropan-2-yl)thiophene-2-sulfonimidamide Step 1: 4-(Prop-1-en-2-yl)thiophene-2-sulfonamide

[002415] To a stirred solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (50 g, 226 mmol) in CF3SO3H (60 ml) in a 500 ml round bottom flask was added TFA (60 ml) by dripping at RT. The resulting solution was stirred for 16 h at 50 °C in an oil bath. The reaction mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8 with aqueous NaOH (3% by weight). The resulting solution was extracted with 3x300 ml of DCM, and the organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 10 g (22%) of the title compound as an off-white solid. MS-ESI: 202 (M-1). Step 2: 4-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide

[002416] To a stirred solution of 4-(prop-1-en-2-yl)thiophene-2-sulfonamide (10 g, 49 mmol) in t-BuOH (40 ml) and acetone (40 ml) in a flask 250 ml round bottom, NMO (11.5 g, 98 mmol) was added, and the resulting solution was stirred for 15 min at RT. Then, a solution of OsO4 (1.24 g, 4.9 mmol) in H2O (60 ml) was added dropwise at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of saturated aqueous Na2S2O3 (50 ml). The resulting solution was extracted with 3x200 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 5.0 g (43%) of the title compound as a yellow oil. MS-ESI: 236 (M-1) Step 3: (S) and (R) 4-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

[002417] The product from the Step above (462, 5.0 g) was separated by

Preparatory chiral HPLC using the following conditions: CHIRALPAK IG, 5*25 cm, 5 µm; Mobile Phase A: CO2, Mobile Phase B: MeOH:ACN=1:1 (2 mM NH 3 -MeOH); Flow rate: 150 ml/min; Gradient: 50% B; UV 220 nm; Rt1: 4.1 min (462F); Rt2: 7.4 min (462S). This resulted in 2.1 g (99% ee) of 462F and 2.2 g (98% ee) of 462S, both as white solids. MS-ESI: 236 (M-1). Step 4: (S)-4-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[002418] To a stirred solution of (S)-4-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide (2.1 g, 8.8 mmol) in THF (50 ml) in To a 250 ml round bottom flask under nitrogen, NaH (60 wt% mineral oil dispersion, 704 mg, 17.6 mmol) was added at 0 °C in a water/ice bath. The resulting solution was stirred for 20 min at RT. To the stirred solution, TBSCl (2.64 g, 17.6 mmol) was added at 0 °C. The resulting solution was stirred overnight at RT. The reaction was then stopped with the addition of 30 ml of water. The resulting solution was extracted with 3x30 ml of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 2.17 g (70%) of the title compound as an off-white solid. MS-ESI: 352 (M+1).

[002419] Steps 5 to 7 used similar procedures to convert compound 442 to Intermediate 195 shown in Scheme 91 to provide Intermediate 199F from compound 463F. MS-ESI: 465 (M+1). Table 45. The Intermediates in the Table below were prepared using similar procedures to convert compound 462F to Intermediate 199F shown in Scheme 94 using 462S.

Interme- Structure IUPAC Name Daily Mass No. [M-H]-Daily Interme-N'-(tert-butyldimethylsilyl)-4-465 ((R)-1-((tert-199S butyldimethylsilyl)oxy)-2-hydroxypropan -2-yl)thiophene-2-sulfonimidamide Scheme 95: Intermediate 200F 5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N'-(tert-butyldimethylsilyl) thiophene-2-sulfonimidamide Step 1: Methyl 5-(Chlorosulfonyl)thiophene-2-carboxylate

[002420] To a stirred solution of methyl thiophene-2-carboxylate (2.13 g, 15 mmol) in CHCl3 (100 mL) in a 250 mL round bottom flask was added ClSO3H (3.5 g, 30 mmol) by dripping at 0 °C in an ice/water bath. The resulting solution was stirred for 1 h at 0 °C. This was followed by the addition of PCl5 (6.25 g, 30 mmol) in por-

tions at 0 °C. The resulting solution was stirred overnight at 50°C. The reaction was quenched by the addition of ice/water (100 ml). The mixture was extracted with DCM (3x100ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 4.0 g (crude product) of the title compound as a yellow oil. MS-ESI: 241/243 (M+1). Step 2: Methyl 5-sulfamoylthiophene-2-carboxylate

[002421] To a stirred solution of methyl 5-(chlorosulfonyl)thiophene-2-carboxylate (4.0 g, crude product) in DCM (20 ml) in a 250 ml round bottom flask was bubbled NH3 at 0 °C for 15 min. The resulting solution was stirred overnight at RT. The resulting mixture was washed with H2O (3x100ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 1.99 g (60% over two steps) of the title compound as a yellow solid. MS-ESI: 222 (M+1). Step 3: 5-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide

[002422] To a stirred solution of methyl 5-sulfamoylthiophene-2-carboxylate (1.0 g, 4.52 mmol) in THF (40 ml) in a 100 ml 3-necked round bottom flask under nitrogen was CH3MgBr in THF (3.0M, 7.5ml, 22.6mmol) is added dropwise at 0°C in an ice/water bath. The resulting solution was stirred overnight at RT. The reaction solution was then quenched by adding saturated NH4Cl (40 ml) at 0 °C. The resulting mixture was extracted with EtOAc (3x40 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 500 mg (50%) of the title compound as a yellow solid. MS-ESI: 222 (M+1). Step 4: 5-(Prop-1-en-2-yl)thiophene-2-sulfonamide

[002423] To a stirred solution of 5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (500 mg, 2.25 mmol) in THF (30 ml) in a 100 ml round bottom flask under nitrogen , Burgess reagent (1.15 g, 4.5 mmol) was added in portions at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was quenched by the addition of H 2 O (10 ml) and extracted with EtOAc (3x20 ml). The organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep TLC (PE/EtOAc=1:2). This resulted in 420 mg (91.5%) of the title compound as a white solid. MS-ESI: 204 (M+1). Step 5: 5-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide

[002424] To a stirred solution of 5-(prop-1-en-2-yl)thiophene-2-sulfonamide (420 mg, 2.06 mmol) in t-BuOH (4.0 mL) and acetone (4. 0 ml) in a 50 ml round bottom flask, NMO (483 mg, 4.12 mmol) was added and the resulting solution was stirred for 15 min at RT. Then, a solution of OsO4 (53 mg, 0.21 mmol) in H2O (3.0 mL) was added dropwise at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of saturated aqueous Na2S2O3 (5.0 ml). The resulting solution was extracted with 3x10 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 245 mg (50%) of the title compound as a yellow oil. MS-ESI: 238 (M+1). Step 6: (S) and (R)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

[002425] The product from Step 5 above (471, 245 mg) was separated by preparatory chiral HPLC using the following conditions: CHIRALPAK AD-H SFC, 5*25 cm, 5 µm; Mobile Phase A: CO2, Mobile Phase B: MeOH:ACN=1:1 (2 mM NH 3 -MeOH); Flow rate: 150 ml/min; Gradient: 50% B; 220 nm; Rt1: 4.1 min (471F); Rt2: 7.4 min (471S). This resulted in 100 mg (99% ee) of 471F and 110 mg (98% ee) of

471S, both as a yellow solid. MS-ESI: 236 (M-1). Step 7: (S)-2-hydroxy-2-(5-sulfamoylthiophen-2-yl)propyl 4-methylbenzenesulfonate

[002426] To a stirred solution of (S)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide (100 mg, 0.42 mmol) in pyridine (8.0 ml) in to a 50 ml round bottom flask, TsCl (239 mg, 1.26 mmol) was added. The resulting solution was stirred for 16 h at RT. The resulting solution was diluted with 20 ml of H2O. The resulting solution was extracted with 3x20 ml of EtOAc, and the organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 125 mg (76%) of the title compound as a yellow oil. MS-ESI: 392 (M+1). Step 8: (S)-5-(1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[002427] To a stirred solution of 2-(benzyloxy)ethan-1-ol (243 mg, 1.6 mmol) in THF (10 ml) in a 50 ml round bottom flask under nitrogen was added NaH (60 % by weight of dispersion in mineral oil, 128 mg, 3.2 mmol) at 0 °C in an ice/water bath. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture, (S)-2-hydroxy-2-(5-sulfamoylthiophen-2-yl)propyl 4-methylbenzenesulfonate (125 mg, 0.32 mmol) was added at 0 °C. The resulting mixture was stirred for 32 h at 35 °C. The reaction was quenched with H 2 O (10 ml) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (2x10 ml), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 113 mg (95%) as a yellow oil. MS-ESI: 372 (M+1).

[002428] Steps 9 through 11 used similar procedures to convert compound 442 to Intermediate 195 shown in Scheme 91 to provide Intermediate 200F from compound

473F. MS-ESI: 485 (M+1). Scheme 96: Intermediate 201 N'-(tert-butyldimethylsilyl)-2-((S)-16-hydroxy-1-phenyl-2,5,8,11,14-pentaoxaheptadecan-16-yl)thiazol-5 -sulfonimidamide

[002429] Steps 1 through 6 used similar procedures to convert compound 471F to Intermediate 200F shown in Scheme 95 to provide Intermediate 201 from compound 289A. MS-ESI: 618 (M+1). Scheme 97:

Intermediate 202 4-Acetyl-N'-(tert-butyldimethylsilyl)thiophene-2-sulfonimidamide Step 1: Methyl 5-(N-(tert-butyldimethylsilyl)sulfamoyl)thiophene-3-carboxylate

[002430] To a stirred solution of methyl 5-sulfamoylthiophene-3-carboxylate (10 g, 45 mmol) in THF (120 ml) in a 250 ml round bottom flask under nitrogen was added NaH (60% by weight of dispersion in mineral oil, 5.42 g, 135 mmol) in portions at 0 °C in an ice/water bath. To the stirred solution, TBSCl (8.17 g, 54 mmol) was added. The resulting solution was stirred overnight at RT. The reaction was quenched by the addition of 100 ml of water. The resulting solution was extracted with 2x200 ml of EtOAc and dried over anhydrous Na 2 SO 4 and concentrated. The resulting mixture was washed with 3 x 100 ml of PE. This resulted in 9.9 g (65%) of the title compound as an off-white solid. MS-ESI: 336 (M+1). Step 2: 5-(N-(tert-Butyldimethylsilyl)sulfamoyl)thiophene-3-carboxylic acid

[002431] To a stirred solution of methyl 5-(N-(tert-butyldimethylsilyl)sulfamoyl)thiophene-3-carboxylate (5.0 g, 14.9 mmol) in MeOH (100 mL) and H 2 O (5.0 ml) in a 250 ml round bottom flask, NaOH (1.19 g, 30 mmol) was added in portions at 0 °C in an ice/water bath. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 ml of H2O. The pH value was adjusted to 3 with HCl (6M). The resulting solution was extracted with 2x150 ml of EtOAc and dried over anhydrous Na2SO4 and concentrated. This resulted in 4.7 g (98%) of the title compound as a yellow solid.

MS-ESI: 322 (M+1). Step 3: N-methoxy-N-methyl-5-sulfamoylthiophene-3-carboxamide

[002432] To a stirred solution of 5-(N-(tert-butyldimethylsilyl)sulfamoyl)thiophene-3-carboxylic acid (4.7 g, 14.6 mmol) in THF (125 ml) in a round-bottomed flask of 250 ml, N,O-dimethylhydroxylamine (1.34 g, 22 mmol), DIEA (5.65 g, 43.8 mmol) and HATU (11.1 g, 29.2 mmol) were added to the mixture. RT. The resulting solution was stirred overnight at RT. The reaction solution was diluted with H2O (100 ml). The mixture was extracted with EtOAc (3x100ml). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 1.65 g (45%) of the title compound as a pale yellow solid. MS-ESI: 251 (M+1). Step 4: 4-Acetyl-N-(tert-butyldimethylsilyl)thiophene-2-sulfonamide

[002433] To a stirred solution of N-methoxy-N-methyl-5-sulfamoylthiophene-3-carboxamide (1.65 g, 6.57 mmol) in THF (60 ml) in a 3-necked round bottom flask of 250 ml under nitrogen, MeMgBr in THF (3M, 8.76 ml, 26.3 mmol) was added by dropping at 0 °C in an ice/water bath. The resulting solution was stirred for 2 h at 40 °C in an oil bath. The reaction was then stopped with the addition of 50 ml of ice/salt. The resulting solution was extracted with 3x100 ml of EtOAc and dried over anhydrous Na 2 SO 4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 1.93 g (92%) of the title compound as a pale yellow solid. MS-ESI: 320 (M+1).

[002434] Steps 5 to 6 used similar procedures to convert compound 442 to Intermediate 195 shown in Scheme 91 to provide Intermediate 202 from compound 483. MS-ESI: 319 (M+1).

Scheme 98: Intermediate 203 N'-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl )thiazol-5-sulfonimidamide Step 1: 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,2-dimethyl-1,3-dioxan-5-ol

[002435] To a stirred solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (1.40 g, 4.55 mmol) in THF (30 ml) in a round bottom flask with 3 100 ml bottlenecks under nitrogen, n-BuLi in hexane (2.5 M, 1.8 ml, 4.55 mmol) was added dropwise at -78 °C in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 30 min at -78 °C. Then to the mixture was added 2,2-dimethyl-1,3-dioxan-5-one (621 mg, 4.78 mmol) in portions at -78 °C. The resulting mixture was stirred for 1 h at -78 °C. The reaction was quenched by the addition of H 2 O (20 ml) at 0°C. The resulting mixture was extracted with EtOAc (3x30ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep TLC (PE/EtOAc 10:1). This resulted in 1.1 g (67%) of the title compound as a brown oil. MS-ESI: 360 (M+1). Step 2: 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazol-5-sulfonic acid

[002436] To a stirred solution of 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,2-dimethyl-1,3-dioxan-5-ol (1,1 g, 3.06 mmol) in THF (30 mL) in a 100 mL 3-necked round bottom flask under nitrogen, n-BuLi in hexane (2.5 M, 2.7 mL, 6.73 mmol) was added. ) by dripping at -78 °C in a liquid nitrogen/EtOH bath. The reaction solution was stirred for 30 min at -78 °C. Then SO2 (g) was bubbled into the solution at -50 °C for 20 min. The resulting solution was allowed to react, with stirring, for a further 2 h at RT. The resulting mixture was concentrated directly under vacuum. This resulted in 1.5 g (crude product) of the title compound as a yellow solid. MS-ESI: 422 (M-1). Step 3: 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazol-5-sulfonyl chloride

[002437] To a stirred solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazol-5- sulfinic acid (1.5 g, crude product) in THF (20 ml) in a 100 ml round bottom flask, NCS (610 mg, 4.59 mmol) was added in portions at 0 °C. The resulting mixture was stirred for 2 h at 0 °C. To the reaction solution, NH3 in THF (0.5M, 50 ml) was added in portions at 0 °C. The resulting mixture was stirred for 2 h at 0 °C. The resulting mixture was concentrated in vacuo. The residue was purified by prep TLC (PE/EtOAc = 7:1). This resulted in 685 mg (51%, over two steps) of the title compound as a brown solid. MS-ESI: 437 (M-1).

[002438] Steps 4 to 6 used similar procedures to convert compound 442 to Intermediate 195 shown in the Scheme

91 to provide Intermediate 203 from compound 487. MS-ESI: 552 (M+1). Scheme 86A: Intermediate 190A N'-(tert-butyldimethylsilyl)-3-ethylthiophene-2-sulfonimidamide

[002439] Steps 1 to 2 used similar procedures to convert compound 485 to compound 487 shown in Scheme 98 to provide compound 407A from compound 405. Step 3: 3-Ethylthiophene-2-sulfonamide and 4-ethylthiophene -2-sulfonamide

[002440] The mixture of 3-ethylthiophene-2-sulfonyl chloride and 4-ethylthiophene-2-sulfonyl chloride from the last step in DCM (200 ml) was bubbled with NH3 at 0 °C for 15 min. The solution was washed with brine (2 x 100 ml), dried over Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 5.0 g (29%) of 408A and 5.1 g (30%) of 408, both as a pale yellow solid. MS-ESI: 190 (M-1).

[002441] Steps 4 to 6 used similar procedures to convert compound 442 to Intermediate 195 shown in Scheme 91 to provide Intermediate 190A from compound 408A.

MS-ESI: 305 (M+1). Scheme 99: Intermediate 204 Step 1: 1-((tert-butyldimethylsilyl)oxy)-2-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)propan-2-ol

[002442] To a stirred solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (3.0 g, 9.7 mmol) in THF (100 ml) in a round bottom flask with 3 250 ml bottlenecks under nitrogen, n-BuLi in hexane (2.5 M, 4.0 ml, 9.7 mmol) was added dropwise at -78 °C in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 30 min at -78 °C. To the mixture, 1-((tert-butyldimethylsilyl)oxy)propan-2-one (1.83 g, 9.7 mmol) was added at -78 °C in 10 min. The resulting solution was stirred for 12 h at RT. The reaction was then stopped with the addition of 10 ml of H2O (100 ml). The resulting mixture was extracted with 3x200 ml of DCM, and the organic layers were combined and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 2.5 g (62%) of the title compound as a yellow oil. MS-ESI: 418 (M+1).

[002443] Steps 2 to 7 used similar procedures to convert compound 485 to Intermediate 203 shown in Scheme 98 to provide Intermediate 204 from compound 490. MS-ESI: 610 (M+1). Step 8: (S) and (R)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-5 -sulfonamide

[002444] The product from the above Step (493, 2.4 g) was separated by preparatory chiral HPLC using the following conditions: CHIRALPAK AD-H SFC, 5*25 cm, 5 µm; Mobile Phase A: CO2, Mobile Phase B: MeOH (2 mM NH3); Flow rate: 200 ml/min; Gradient: 50% B; UV 220 nm; Rt1: 4.3 min (493A); Rt2: 6.9 min (493B); This resulted in 1.1 g of 493A (99% ee) and 1.0 g of 493B (99% ee). MS-ESI: 495 (M-1). Table 46. The Intermediates in the Table below were prepared using similar procedures to convert compound 493 to Intermediate 204 shown in Scheme 99 using 493A and 493B. Interme- Mass Exa- Structure IUPAC name diary no. [MH]- (R) or (S) N'-(tert-butyldimethylsilyl)-2-(1-((tert-Intermebutyldimethylsilyl)oxy)-2-daily hydroxypropan-2-yl)-4-610 204A (((tert-butyldimethylsilyl)oxy)methyl)thiazol-5-sulfonimidamide

Interme- Mass Exa- Structure IUPAC name daily no. [MH]-(S) or (R) N'-(tert-butyldimethylsilyl)-2-(1-((tert-Intermebutyldimethylsilyl)oxy)-2- daily hydroxypropan-2-yl)-4-610 204B (((tert-butyldimethylsilyl)oxy)methyl)thiazol-5-sulfonimidamide Scheme 100: Intermediate 205 N'-(tert-butyldimethylsilyl)-2-ethylthiazol-5-sulfonimidamide Step 1: 2-ethylthiazol-5-sulfonamide

[002445] To a stirred solution of 2-acetylthiazol-5-sulfonamide (1.0 g, 4.8 mmol) in ethylene glycol (20 mL) in a 50 mL round bottom flask was added NH2NH2.H2O (1. 2 g, 24 mmol) by dripping at RT. The resulting mixture was stirred for 2 h at 150 °C under nitrogen. The mixture was allowed to cool to RT. To the above mixture, KOH (544 mg, 9.6 mmol) was added at RT. The resulting mixture was stirred for a further 1.5 h at 150 °C. The residue was eluted from a silica gel column with DCM/MeOH (15:1). This resulted in 430 mg (46%) of the title compound as a yellow solid. MS-ESI: 191 (M-1).

[002446] Steps 2 to 4 used similar procedures to convert compound 442 to Intermediate 195 shown in Scheme 91 to provide Intermediate 205 from compound 496. MS-ESI: 306 (M+1). Scheme 101: Intermediate 206 (6R)-N'-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonimidamide Step 1: 1,2-dihydropyrazol-5-one

[002447] To a 5 L 4-neck flask containing a solution of methyl (E)-3-methoxyacrylate (2000 g, 17.2 mol) in MeOH (2.0 L) was added hydrazine hydrate (921 g, 18.4 mol) by dripping at RT under nitrogen. The resulting mixture was stirred for 90 min at 60 °C under nitrogen. The resulting mixture was concentrated under reduced pressure. This resulted in the title compound (1467 g, 68% by weight, yield 69%) as an off-white solid. MS-ESI: 85 (M+1). Step 2: 2-Acetyl-1,2-dihydropyrazol-5-one

[002448] To a 10 L 4-neck flask containing a solution of 1,2-dihydropyrazol-5-one (1467 g, 68% by weight, 11.9 mol) in pyridine (6.0 L ), Ac2O (1214 g, 11.9 mol) was added at RT under nitrogen. The resulting mixture was stirred for 1.5 h at 95 °C under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was a slurry with MeOH (1x3000 ml). The resulting mixture was filtered, the filter cake was washed with MeOH (1x500 ml). The filter cake was dried under reduced pressure. This resulted in the title compound (1630 g, 78% by weight, 85%) as an off-white solid. MS-ESI: 127 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 3.0 Hz, 1H), 6.00 (d, J = 3.0 Hz, 1H), 2.48 (s, 3H ), 2.44 (s, 1H). Step 3: (R)-2-Acetyl-1-(oxiran-2-ylmethyl)-1,2-dihydropyrazol-5-one

[002449] To a 10 L 4-neck flask containing a solution of 2-acetyl-1,2-dihydropyrazol-5-one (400 g, 78% by weight, 3.17 mol) and R-glycidol ( 246 g, 3.33 mol) in THF (4.0 L), to the stirred solution was added PPh3 (915 g, 3.49 mol). To the above mixture, TMAD (705 g, 3488 mmol) was added in portions at 0 °C. The resulting mixture was stirred for a further 1 h at RT. The resulting mixture was quenched with 1x4.0 L of water. The aqueous layer was extracted with EtOAc (3x1.0 L). The organic layers were combined and washed with brine (1 L), dried over Na2SO4 and concentrated under reduced pressure. The crude product was slurry in PE/EtOAc (10:1) (16 L) for 4 h. The resulting mixture was filtered. The filter cake was washed with PE/EtOAc (10:1) (1x1000 ml). The filtrate was concentrated under reduced pressure. This resulted in the title compound (470 g, 84% by weight, 87%) as an off-white solid. MS-ESI: 183 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 3.0 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 4.56 (dd, J = 11.8, 2.7 Hz, 1H), 4.02 (dd, J = 11.8, 6.8 Hz, 1H), 3.40-3.34 (m, 1H), 2.86 ( dd, J = 5.1, 4.3 Hz, 1H), 2.74 (dd, J = 5.1, 2.6 Hz, 1H), 2.54 (s, 3H). Step 4: (R)-2-acetyl-1-(3-chloro-2-hydroxypropyl)-1,2-dihydropyrazole-

5-one

[002450] A solution of (R)-2-acetyl-1-(oxiran-2-ylmethyl)-1,2-dihydropyrazol-5-one (R)-2-acetyl-1-(oxiran-2-ylmethyl)-1,2-dihydropyrazol-5-one ( 500 g, 84% by weight, 2.74 mol) in THF (2.5 L), to the stirred solution was added AcOH (494 g, 8233 mmol) dropwise and LiCl (186 g, 4391 mmol) in portions. at 0 °C under nitrogen. The resulting mixture was stirred for 16 h at RT under nitrogen. The reaction was quenched with water at RT. The aqueous layer was extracted with EtOAc (3x3.0 L). The organic layers were combined and washed with 2x3.0 L of saturated NaHCO3 and 5.0 L of brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. This resulted in the title compound (552 g, 82% by weight, 90% yield) as an off-white solid. MS-ESI: 219 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 3.0 Hz, 1H), 6.02 (d, J = 3.0 Hz, 1H), 4.44 (d, J = 5 .0 Hz, 2H), 4.29-4.23 (m, 1H), 3.81-3.67 (m, 2H), 2.61 (s, 3H). Step 5: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol

[002451] A solution of (R)-2-acetyl-1-(3-chloro-2-hydroxypropyl)-1,2-dihydropyrazol-5- One (500 g, 82 wt%, 2.29 mol) in DMF (5.0 L), to the stirred solution was added K2CO3 (948 g, 6.86 mol) under nitrogen. The resulting mixture was stirred for 16 h at 135 °C under nitrogen and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to provide (152 g, 58% yield) of the title compound as an off-white solid. MS-ESI: 141 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 7.11 (d, J = 2.1 Hz, 1H), 5.31 (d, J = 2.1 Hz, 1H), 4.19 - 4.12 (m, 1H), 4.12 - 3.98 (m, 3H), 3.90 - 3.81 (m, 1H). Step 6: (R)-6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate

[002452] To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-

b][1,3]oxazin-6-ol (55.0 g, 392 mmol) in MeCN (825 ml) in a 3-neck 2 L round bottom flask under nitrogen, pyridine (93. 1 g, 1.18 mol) and DMAP (4.79 g, 39.2 mmol). This was followed by the addition of acetyl chloride (43.1 g, 549 mmol) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at RT. LCMS showed that the reaction was complete. The resulting mixture was directly concentrated. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 58 g (81%) of the title compound as a pale yellow solid. MS-ESI: 183 (M+1). 1H NMR (400 MHz, CDCl 3 ) δ 7.39 (d, J = 2.0 Hz, 1H), 5.57 (d, J = 2.0 Hz, 1H), 5.45-5.36 (m , 1H), 4.49-4.41 (m, 1H), 4.40-4.27 (m, 2H), 4.24 (dd, J = 12.1, 1.5 Hz, 1H), 2.14 (s, 3H). Step 7: (R)-6-acetoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid

[002453] To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate (58.0 g, 318 mmol ) in DCM (120 mL) in a 2 L 3-necked round bottom flask under nitrogen, chlorosulfonic acid (81.3 g, 700 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 12 h at RT. LCMS showed that the conversion was complete. The reaction mixture was used directly in the next step. MS-ESI: 263 (M+1). Step 8: (R)-3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate

[002454] To a stirred solution of (R)-6-acetoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid in DCM (crude product from step 7) in a 2 L 3-necked round bottom flask under nitrogen, pyridine (55.1 g, 696 mmol) was added dropwise at 0 °C. Thereto, PCl5 (144 g, 696 mmol) was added in portions at 0 °C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 1 L of water/ice. The solution re-

The resultant was extracted with 3x300 ml of EtOAc. The resulting mixture was washed with 2x500 ml of NaHCO3 and 1x500 ml of H2O. The resulting mixture was washed with 1x500 ml of NaCl (aq.). The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 76 g (crude product) of the title compound as a pale yellow solid. MS-ESI: 281/283 (M+1). Step 9: (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

[002455] To a stirred solution of NH 3 in THF (1M, 730 ml) in a 3 L round bottom flask was added (R)-3-(chlorosulfonyl)-6,7-di-acetate. hydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl (73.0 g, 260 mmol) in several batches. The flask was then filled with NH3 (balloon). The resulting solution was stirred overnight at 40 °C in an oil bath. After the reaction was complete, the solids were removed by filtration. The filtrate was concentrated. The residue was diluted with NH3 (7M in MeOH, 730 ml). The resulting solution was stirred for 2 h at RT. LC showed that the reaction was complete. The MeOH solution was concentrated under reduced pressure to a final volume of about 100 ml. Et2O (360 ml) was charged to the resulting solution and stirred for 30 min. The mixture was filtered, and the cake was washed with Et2O (100 ml). The white solid was dried under vacuum. This resulted in 37 g (53% for 3 steps) of the title compound as a white solid. MS-ESI: 220 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.06 (s, 2H), 5.64 (d, J = 2.3 Hz, 1H), 4.30 (s , 3H), 4.30 - 4.18 (m, 1H), 4.00 - 3.90 (m, 1H). Step 10: (R)-N-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b]-[1,3] oxazine-3-sulfonamide

[002456] To a stirred solution of (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (500 mg, 2, 28 mmol) in DMF (20 ml) in a 50 ml round bottom flask was added

DBU (2.08 g, 13.7 mmol) and TBDPSCl (5.02 g, 18.2 mmol) at 0 °C. The resulting solution was stirred for 2 h at RT and then diluted with 30 ml of H2O. The resulting solution was extracted with 3x100 ml of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 530 mg (33.3%) of the title compound as a solid. MS-ESI: 696 (M+1). Step 11: (6R)-N'-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonimidamide

[002457] To a stirred solution of PPh3Cl2 (759 mg, 2.28 mmol) in DCE (30 mL) in a 100 mL 3-necked round bottom flask under nitrogen was added DIEA (492 mg, 3.81 mmol ) at 0°C. The resulting solution was stirred for 10 min at RT. So, (R)-N-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 3-sulfonamide (530 mg, 0.76 mmol) in CHCl 3 (10 ml) was added at 0 °C. The resulting solution was stirred for 30 min at 0 °C. Then, NH3 (g) was bubbled into the reaction mixture for 15 min at 0 °C. The resulting solution was stirred for 2 h at RT. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 400 mg (75.6%) of the title compound as a white solid. MS-ESI: 695 (M+1). Scheme 102: Intermediate 207

(6R)-N'-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide Step 1: (R )-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

[002458] To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (40 g, 285 mmol) in DMF ( 400 mL) in a 1 L 4-necked round bottom flask, NaH (60% oil dispersion, 13.7 g, 342 mmol) was added in portions at 0 °C. The resulting mixture was stirred for 1 h at RT. To the above mixture, MeI (48.7 g, 343 mmol) was added dropwise at RT. The resulting mixture was stirred for a further 2 h at RT. The reaction was quenched with AcOH (3.66 g, 57.1 mmol) at 0 °C and concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:2) to afford the title compound (34.6 g, 79%) as a pale yellow solid. MS-ESI: 155 (M+1).

[002459] Steps 2 to 4 used similar procedures to convert compound 505 to compound 508 shown in Scheme 101 to provide compound 513 from compound 510. MS-ESI: 232 (M-1).

[002460] Steps 5 to 6 used similar procedures to convert compound 442 to intermediate 195 shown in Scheme 91 to provide intermediate 207 from compound 513. MS-ESI: 347 (M+1).

Scheme 103: Intermediate 208 ((6R)-3-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6 tert-butyl -yl)(methyl)carbamate

[002461] Steps 1 to 5 used similar procedures to convert compound 499 to compound 504 shown in Scheme 101 to provide compound 517 from compound 499. MS-ESI: 141 (M+1). Step 6: (S)-6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate

[002462] To a stirred solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (40 g, 285 mmol) in pyridine ( 280 ml) in a 500 ml 3-neck flask under nitrogen was added MsCl (39 g, 343 mmol) by drip at RT. The resulting mixture was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure.

gives. The crude product was diluted with 500 ml of water. The resulting mixture was extracted with EtOAc (3x300 ml). The combined organic layers were washed with water (3x200ml) and brine 1x100ml, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (57 g, 92%) as an off-white solid. MS-ESI: 219 (M+1). Step 7: (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

[002463] To a stirred solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate (46 g, 211 mmol) in DMF (313 ml) in a 1 L 3-neck flask under nitrogen, NaN3 (21 g, 316 mmol) was added at RT. The resulting mixture was stirred for 6 h at 80 °C. LCMS showed that the reaction was complete. It was used directly in the next step. MS-ESI: 166 (M+1). Step 8: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine

[002464] To a stirred solution of (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine in DMF from the last step was added MeOH ( 313 ml) followed by Pd/C (10% by weight, 10 g) under nitrogen. The mixture was hydrogenated at RT for 5 h under a hydrogen atmosphere using a hydrogen balloon. LCMS showed the reaction to be complete. The mixture was filtered through a Celite filter and concentrated under reduced pressure to remove low boiling solvent. This resulted in the title compound in DMF solution, which was used directly in the next step. MS-ESI: 140 (M+1). Step 9: tert-Butyl (R)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

[002465] To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine in DMF from the last step was added MeOH ( 313 ml) followed by TEA (50 g, 496 mmol) and di-tert-butyl dicarbonate (79 g, 364 mmol) at RT under nitrogen. The resulting mixture was stirred for 16 h at RT. The resulting mixture was quenched with 500 ml of water. The resulting mixture was extracted with EtOAc (3x300 ml). The combined organic layers were washed with H2O (2x600ml) and brine (1x600ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (45.9 g, 91%, over 3 steps) as an off-white solid. MS-ESI: 240 (M+1). Step 10: tert-Butyl (R)-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

[002466] To a stirred solution of tert-butyl (R)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (140 g , 585 mmol) in MeCN (2.1 L) in a 3 L 3-neck flask under nitrogen, NBS (115 g, 644 mmol) was added at 0 °C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was diluted with 2000 ml of water. The resulting mixture was extracted with EtOAc (3 x 800 ml). The combined organic layers were washed with brine (1x800 ml), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (167 g, 90%) as an off-white solid. MS-ESI: 318/320 (M+1). Step 11: tert-Butyl (R)-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate

[002467] To a stirred solution of tert. -butyl (170 g, 534 mmol) in DMF (1.19 L) In a 3 L 3-neck flask under nitrogen, sodium hydride (60% oil dispersion, 26 g, 650 mmol) was added. in portions at 0 °C. The mixture was stirred for 1 h at 0 °C. Then MeI (379 g, 2.67 mol) was added, and the mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (3*800 ml), the organic layers were washed with H2O (3x500 ml) and brine.

(1x800 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1) to afford the title compound (153 g, 86%) as an off-white solid. MS-ESI: 332/334 (M+1). Step 12: (R)-(3-(benzylthio)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate tert. butyl

[002468] To a stirred solution of (R)-(3-bromo-6,7-dihydro-5H-pyrazolo-[5,1-b][1,3]oxazin-6-yl)(methyl) tert-butyl carbamate (130 g, 391 mmol) in THF (1.3 L) in a 3 L 3-neck flask under nitrogen was added n-BuLi (188 mL, 470 mmol, 2.5 mol /l) by dripping at -78 °C. The resulting mixture was stirred for 1 h at -78 °C. To the above mixture, bis(phenylmethyl) disulfide (145 g, 587 mmol) in THF (300 ml) was added dropwise at -78°C. The resulting mixture was stirred for a further 2 h at RT. The reaction was quenched by the addition of saturated NH4Cl (aq.) (500 ml) at RT. The resulting mixture was extracted with EtOAc (3 x 500 ml). The combined organic layers were washed with brine (1x800 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (6:1) to afford the title compound (106 g, 72%) as an off-white solid. MS-ESI: 376 (M+1). Step 13: (R)-(3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl) carbamate tert. butyl

[002469] To a stirred solution of (R)-(3-(benzylthio)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)-( tert-butyl methyl)carbamate (110 g, 293 mmol) in AcOH (3.67 L)/H2O (1.83 L) in a 10 L 3-neck flask under nitrogen was added NCS (155 g , 1.17 mol) in portions at 0°C. The resulting mixture was stirred for 1 h at RT. The reaction was quenched with water/ice at RT. The resulting mixture was extracted with MTBE (3 x 1 L). The combined organic layers were washed with water (2 x 1.0 L), NaHCO 3 (2 x 1.0 L) and brine (1 x 1 L), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (80 g, crude product) as a yellow solid. MS-ESI: 374 (M+Na). Step 14: tert-Butyl (R)-methyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

[002470] A stirred solution of (R)-(3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl) tert-butyl carbamate (80 g, 227 mmol) in NH 3 in THF (1 M, 800 ml, 800 mmol) in a 2 L 3-neck flask under nitrogen was charged with (balloon). The resulting mixture was stirred overnight at 60°C. The reaction mixture was quenched by adding water and extracted with MTBE (3 x 800 ml), the organic layers were washed with H 2 O (3 x 500 ml) and brine (1 x 800 ml), dried with anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The precipitated solid was a slurry with MTBE (1x100 ml). This resulted in the title compound (36 g, for 2 steps) as an off-white solid. MS-ESI: 333 (M+1).

[002471] Steps 15 to 16 used similar procedures to convert compound 442 to intermediate 195 shown in Scheme 91 to provide intermediate 208 from compound 526. MS-ESI: 446 (M+1). Scheme 104:

Intermediate 209 N'-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)pyridine-2-sulfonimidamide Step 1: Methyl 6-sulfamoylpicolinate

[002472] To a stirred solution of 6-bromopyridine-2-sulfonamide (5.0 g, 21 mmol) in MeOH (200 ml) in a 100 ml pressure tank reactor was added Pd(dppf)Cl2 (1.5 g, 2.1 mmol), Pd(PPh3)4 (2.4 g, 2.1 mmol) and TEA (10.7 g, 105 mmol) under nitrogen. The pressure tank reactor was evacuated and refilled three times with carbon monoxide. The reaction mixture was stirred overnight at 80 °C under a carbon monoxide atmosphere (10 atm). The resulting mixture was concentrated under reduced pressure. The residue was eluted from a silica gel column with PE/EtOAc (1:2). This resulted in 1.8 g (39%) of the title compound as a pale yellow solid. MS-ESI: 215 (M-1). Step 2: 6-(2-hydroxypropan-2-yl)pyridine-2-sulfonamide

[002473] To a stirred solution of methyl 6-sulfamoylpyridine-2-carboxylate (1.8 g, 8.3 mmol) in THF (180 ml) under nitrogen was added MeMgBr (3 M in THF, 28 ml , 83 mmol) by dripping at 0°C. The solution was stirred overnight at RT under nitrogen. The reaction was quenched by adding 50 ml of water, then acidified to pH 6 with concentrated HCl. The resulting mixture was extracted with EtOAc (3x200ml). The combined organic layers were washed with brine (3x100 ml), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (5:1). This resulted in the title compound 0.90 g (50%) as an off-white solid. MS-ESI: 215 (M-1).

[002474] Steps 3 to 4 used similar procedures to convert compound 442 to intermediate 195 shown in Scheme 91 to provide intermediate 209 from compound 530. MS-ESI: 330 (M+1). Scheme 105: Intermediate 210 N'-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-ethyl-1H-pyrazol-3-sulfonimidamide Step 1: 1-ethyl-3-nitro- Methyl 1H-pyrazole-5-carboxylate

[002475] To a stirred solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (300 mg, 1.75 mmol) in DMF (10 ml) in a 50 ml round bottom flask was added K2CO3 ( 485 mg, 3.5 mmol) and bromoethane (382 mg, 3.5 mmol) in portions at RT. The resulting solution was stirred for 4 h at 30 °C. The resulting solution was diluted with 10 ml of H2O. The resulting solution was extracted with 4x20 ml of EtOAc, and the organic layers were combined and dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 305 mg (87%) of the title compound as a pale yellow solid. MS-ESI: 200 (M+1).

[002476] Steps 2 through 7 used similar procedures to con-

pouring compound 445 into intermediate 196 shown in Scheme 92 to provide intermediate 210 from compound 532. MS-ESI: 433 (M+1). Scheme 106: Intermediate 211 tert-Butyl (S)-(amino(1-(fluoromethyl)-1H-pyrazol-3-yl)(oxo)-λ6-sulfanoylidene)carbamate Step 1: 1-((2- (Trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[002477] To a stirred solution of 1H-pyrazole (10 g, 146.9 mmol) in dry THF (400 ml) under nitrogen was added NaH (60 wt%, mineral oil dispersion, 6.17 g, 154 mmol) in portions at 0 °C. The reaction mixture was stirred for 15 min at RT. To the above mixture, SEMCl (26.5 ml, 150 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred for 2 h at RT. The reaction was quenched with water (200 ml) and extracted with EtOAc (3x400 ml), and the organic layers were combined, washed with water (400 ml) and brine (400 ml), dried over MgSO4, filtered and concentrated in vacuo. . The residue was eluted from silica gel with 5~50% EtOAc in hexane. This resulted in 23.5 g (81%) of the title compound as a clear oil. MS-ESI: 199 (M+1). Step 2: (S)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-sulfinamide

[002478] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (7.5 g, 37.8 mmol) in dry THF (200 mL) under nitrogen was added

of n-BuLi in hexane (2.5M, 16 ml, 40 mmol) by dripping at -78 °C, and the reaction mixture was stirred for 2 h at -78 °C. To the above solution, a solution of Mts-S,R,R-Aux (15 g, 39.7 mmol) in dry THF (200 ml) kept at -78°C was cannulated. The mixture was stirred for 3 h at -78 °C. To the above mixture, KHMDS in THF (1M, 75.6 ml, 75.6 mmol) was added dropwise at -78 °C. The reaction was warmed to 0 °C. The reaction mixture was quenched with formic acid in THF (1M, 113 ml, 113 mmol) by droplet at 0°C. The mixture was concentrated in vacuo, and the residue was dissolved in DCM and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was eluted from silica gel with EtO-Ac/hexane (10%~100%). This resulted in 5.6 g (57%, 99%ee Chiralpak AD, 70:30 hexane/EtOH + 0.1% DEA) of the title compound as a beige waxy solid. MS-ESI: 262 (M+1). Step 3: tert-Butyl (S)-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)sulfinyl)carbamate

[002479] To a solution of (S)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-sulfinamide (5.5 g, 21 mmol) in dry THF (200 ml) under n. - trogen, t-BuOLi in THF (1M, 43.1 ml, 43.1 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 20 min at 0 °C. To the above mixture, Boc2O (4.59 g, 21 mmol) was added in portions, and the reaction was stirred for 2 h at 0 °C. The reaction was quenched with formic acid in THF (1M, 44 ml, 44 mmol) at 0 °C. The mixture was concentrated under vacuum. The residue was eluted from silica gel with 5~50% EtOAc in hexane. This resulted in 6.0 g (79%, 99%ee Chiralpak IG, 70:30 hexane/EtOH + 0.1% DEA) of the title compound as a colorless oil. MS-ESI: 362 (M+1) Step 4: (S)-(amino(oxo)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-λ6-sulfanoylidene) tert-butyl carbamate

[002480] To a solution of (S)-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-

tert-butyl pyrazol-5-yl)sulfinyl)carbamate (5.75 g, 15.9 mmol) in dry DME (100 mL), TCCA (1.85 g, 7.95 mmol) was added in portions. at 0°C. The mixture was stirred for 1 h at 0 °C. This reaction solution was cannulated into a flask containing NH3 (7M in MeOH, 22.7 ml, 160 mmol) at 0 °C, and the mixture was stirred for 4 h at the same temperature. The reaction mixture was diluted with DCM, filtered through a plug of silica washed with EtOAc and concentrated. The residue was eluted from silica gel with 10~70% EtOAc in hexane. This resulted in 3.0 g (50%) of the title compound as a white solid. MS-ESI: 377 (M+1). Step 5: tert-Butyl (S)-(amino(oxo)(1H-pyrazol-5-yl)-λ6-sulfanoylidene)carbamate

[002481] To a solution of tert-butyl (S)-(amino(oxo)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-λ6-sulfaneylidene)carbamate ( 2.8 g, 7.44 mmol) in EtOH (50 mL), aq. (3M, 24.8 ml, 74.4 mmol) by dripping at RT. The mixture was stirred for 2 h at RT. The reaction was cooled to 0 °C and quenched with saturated NaHCO3. The mixture was extracted with EtOAc (3x100 ml), and the organic layers were combined. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was eluted from silica gel with 0 to 20% MeOH in DCM. This resulted in 755 mg (41%, 97.5%ee Chiralpak IG, 85:15 hexane/EtOH + 0.1% DEA) of the title compound as a white foam. MS-ESI: 247 (M+1). Step 6: tert-Butyl (S)-(amino(1-(fluoromethyl)-1H-pyrazol-3-yl)(oxo)-λ6-sulfanoylidene)carbamate

[002482] To a solution of tert-butyl (S)-(amino(oxo)(1H-pyrazol-5-yl)-λ6-sulfanoylidene)carbamate (45mg, 0.18mmol) in dry THF (2ml ) under nitrogen, t-BuOK in THF (1M, 384 µl, 0.38 mmol) was added at RT. The mixture was stirred for 30 min at RT. To the above mixture, CH2FI (14 µl, 0.20 mmol) was added. The mixture was stirred over the weekend. The reaction was quenched with formic acid in THF (1M, 385 µl), and the mixture was concentrated in vacuo. The residue was eluted from silica gel with 0 to 25% MeOH in DCM. This resulted in 27 mg (54%, 98%ee Chiralpak IG, 80:20 hexane/EtOH + 0.1% DEA) of the title compound as a white solid. MS-ESI: 279 (M+1).

[002483] Schemes for Amino Pyridine Intermediates: Schemes 107 to 115 illustrate the preparation of amino pyridine intermediates. Scheme 107: Intermediate 212 2-(Difluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 2-(Difluoromethyl)-6,7-dihydro-5H-cyclopenta [b]pyridin-4-amine

[002484] To a stirred solution of 2-aminocyclopent-1-ene-1-carbonitrile (20 g, 185 mmol) in DCE (400 ml) in a 1 L round bottom flask under nitrogen was added 1,1- difluoropropan-2-one (17.4g, 185mmol) and BF3.Et2O (47% by weight, 25g, 370mmol) dripped at 0°C. The resulting solution was stirred for 4 h at 80 °C in an oil bath. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 500 ml of water. The pH value of the solution was adjusted to 8 with K2CO3 (sat.). The resulting solution was extracted with 3x500 ml of EtOAc. The organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.71 g (5.0%) of the title compound as a yellow solid. MS-ESI: 185 (M+1). Scheme 108: Intermediate 213 3-Ethyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002485] Step 1 used similar procedures to convert compound 544 to intermediate 212 shown in Scheme 107 to provide compound 546 from compound 545. MS-ESI: 217 (M+1). Step 2: 3-Bromo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002486] To a stirred solution of 2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (950 mg, 4.4 mmol) in MeCN (20 ml),

NBS (1.56 g, 8.8 mmol) was added. The resulting solution was stirred for 1 h at RT under nitrogen. The reaction was then stopped with the addition of 20 ml of saturated Na2S2O3 (aq). The resulting solution was extracted with 3x50 ml of EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1/5). This resulted in 1.8 g (83%) of the title compound as a yellow solid. MS-ESI: 295, 297 (M+1). Step 3: 2-(2,2,2-Trifluoroethyl)-3-vinyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002487] To a stirred solution of 3-bromo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1.0 mg, 3 .4 mmol) in dioxane (100 ml) and water (10 ml), Cs2CO3 (2.2 g, 6.8 mmol), 4,4,5,5-tetramethyl-2-vinyl-1, 3,2-dioxaborolane (1.0 g, 6.8 mmol) and Pd(dppf)Cl 2 (250 mg, 0.34 mmol) under nitrogen. The resulting solution was stirred overnight at 90 °C under nitrogen. The reaction mixture was then diluted with 100 ml of water. Solids were removed by filtration. The filtrate was extracted with 3x200 ml of EtOAc, the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 1.0 g (73%) of the title compound as a yellow solid. MS-ESI: 243 (M+1). Step 4: 3-Ethyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002488] To a stirred solution of 2-(2,2,2-trifluoroethyl)-3-vinyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 2.06 mmol) in MeOH (50 ml), Pd/C (10% by weight, 50 mg) was added under nitrogen in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen with a balloon. The solids were removed by filtration.

dog. The resulting solution was concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 400 mg (80%) of the title compound as a yellow solid. MS-ESI: 245 (M+1). Scheme 109: Intermediate 214 2-(1-Fluorocyclopropyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002489] Steps 1 to 3 used similar procedures to convert compound 545 to compound 548 shown in Scheme 108 to provide intermediate 214 from compound 549. MS-ESI: 207 (M+1). Scheme 110: Intermediate 215 3-Cyclopropyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-

amine Step 1: 3-cyclopropyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002490] To a stirred solution of 3-bromo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1.0 g, 3 .4 mmol) in toluene (20 ml) and water (2.0 ml), cyclopropylboronic acid (1.2 g, 13.6 mmol) and Na2CO3 (1.1 g, 10.2 mmol) were added portionwise to the RT. To the above solution, Pd(dppf)Cl2 (20 mg, 0.03 mmol) and Ruphos (20 mg, 0.03 mmol) were added under nitrogen. The mixture was stirred overnight at 90°C under nitrogen; LCMS showed that the starting material was consumed. The resulting mixture was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EA (6:1). This resulted in 600 mg (69%) of the title compound as a yellow solid. MS-ESI: 257 (M+1). Table 47. The Intermediates in the Table below were prepared using similar procedures to convert compound 547 to Intermediate 215 shown in Scheme 110 from suitable starting materials. Interme- Exact Mass Structure IUPAC name daily no. [MH]- 3-cyclopropyl-2- Interme-(trifluoromethyl)-6,7-daily hydro-5H- 243 216 cyclopenta[b]pyridin-4-amine Interme-2 -Methyl-3-phenyl-6,7-daily hydro-5H- 217 225 cyclopenta[b]pyridin-4-(from amine of 558)

Scheme 111: Intermediate 218A and Intermediate 218B 3,5-Dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine and 3,6-dimethyl-2-(trifluoromethyl) )-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 3-Methylhexanediamide

[002491] To a stirred solution of 3-methyladipic acid (10 g, 62.4 mmol) in DCM (300 ml), SOCl 2 (100 ml, 841 mmol) was added dropwise with stirring at 0 °C under nitrogen. The resulting solution was stirred for 4 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 11 g (crude product) of 3-methylhexanedioyl dichloride as a brown oil, which was dissolved in THF (50 ml). This solution was designated "A". To the stirred solution of NH 3 in THF (0.5M, 300 ml), solution A (50 ml prepared above) was added dropwise at 0°C. The resulting solution was stirred for 3 h at RT. The reaction was then stopped with the addition of 20 ml of MeOH. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 9.72 g (98%) of the title compound as a white solid. MS-ESI: 159 (M+1). Step 2: 3-Methylhexanedinitrile

[002492] To a stirred solution of 3-methylhexanediamide (10 g, 63.2 mmol) in MeCN (200 mL), POCl 3 (48.5 g, 316 mmol) was added dropwise at 0 °C. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 20 ml of water/ice. The resulting solution was extracted with 3x200 ml of DCM acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 3.58 g (46%) of the title compound as a yellow oil. MS-ESI: 121 (M-1). Step 3: Mixture of 2-amino-5-methylcyclopent-1-ene-1-carbonitrile and 2-amino-4-methylcyclopent-1-ene-1-carbonitrile

[002493] To a stirred solution of 3-methylhexanedinitrile (3g, 24.6mmol) in THF (100ml), was added NaH (60% by weight dispersion in mineral oil, 2.95g, 74 mmol) in portions at 0 °C under nitrogen. The resulting solution was stirred overnight at 80°C. The reaction was then quenched by the addition of 50 ml of water. The resulting solution was extracted with 3x200 ml of EtOAc, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 1.65 g (crude product) of mixture (1:1) of the title compound as a yellowish brown solid. MS-ESI: 121 (M-1) for both.

[002494] Step 4 used similar procedures to convert compound 544 to intermediate 212 shown in Scheme 107 to provide intermediate 218A and 218B from compound 555A and 555B. MS-ESI: 231 (M+1) for both. Scheme 112: Intermediate 219

2-Methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 2-Methyl-6,7-dihydro-5H-cyclopenta[b] pyridin-4-amine

[002495] To a stirred solution of acetone (34.8 g, 6.0 mol) in toluene (50 ml), was added 2-aminocyclopent-1-ene-1-carbonitrile (10.8 g, 100 mmol ) and ZnCl 2 (1.5 g, 110 mmol) at RT. The resulting solution was stirred for 16 h at 100 °C under nitrogen. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 2.2 g (14.9%) of the title compound as a yellow solid. MS-ESI: 149 (M+1). Step 2: 3-Bromo-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002496] To a stirred solution of 2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (2.2 g, 14.8 mmol) in MeCN (30 ml) was NBS (3.17 g, 18 mmol) is added. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched with saturated Na 2 SO 3 (aq., 5.0 ml), then diluted with water (50 ml), extracted with DCM (3x100 ml). The combined organic layers were dried over Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.3 g (39%) of the title compound as a dark brown solid. MS-ESI: 227/229 (M+1). Step 3: 2-Methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002497] To a stirred solution of 3-bromo-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (100 mg, 0.44 mmol) in DMF (2.0 ml)/NMP (2.0 ml) in a sealed tube under nitrogen, trimethyl-(trifluoromethyl)silane (170 mg, 1.3 mmol), CuI (168 mg, 0.88 mmol) and KF ( 51.2 mg, 0.88 mmol). The resulting solution was stirred overnight at 80°C. The residue was eluted from a silica gel column with EtOAc/PE (1:1) and further purified by preparatory TLC. This resulted in 3.0 mg (3.0%) of the title compound as an off-white solid. MS-ESI: 217 (M+1). Scheme 113: Intermediate 220 8-Amino-1,5,6,7-tetrahydrodicyclopenta[b,e]pyridin-3(2H)-one Step 1: (3-hydroxy-1,2,3,5,6 2,2,2-Trichloroethyl ,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

[002498] To a stirred solution of HCl in 1,4-dioxane (4M, 40 ml) was added (3-((tert-butyl-dimethylsilyl)oxy)-1,2,3,5,6,7 2,2,2-trichloroethyl-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (4.3 g, 9.0 mmol) at RT. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 2.45 g (75%) of the title compound as an off-white solid. MS-ESI: 365/367/369 (M+1). Step 2: 2,2,2-Trichloroethyl (3-oxo-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

[002499] To a stirred solution of 2,2,2-trichloroethyl (3-hydroxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (643 mg, 1.76 mmol) in DCM (25 ml), MnO 2 (764 mg, 8.79 mmol) was added portionwise at RT. The resulting solution was stirred for 2 h at RT.

Solids were removed by filtration. The resulting mixture was concentrated. This resulted in 630 mg (crude product) of the title compound as a pale yellow solid. MS-ESI: 363/365/367 (M+1). Scheme 114: Intermediate 221 3-Methyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 3-Methyl-2-( 2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002500] To a stirred solution of 3-bromo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 1.69 mmol) in dioxane (15 ml) in a sealed 40 ml tube under nitrogen, 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.06 g, 8.47 mmol), K2CO3 (706 mg, 5.08 mmol) and Pd(dtbpf)Cl2 (221 mg, 0.034 mmol). The reaction mixture was stirred overnight at 85 °C. The reaction was quenched with H2O (15 ml). The mixture was extracted with 3x30 ml of EtOAc, and the organic layers were combined. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (2/1). This resulted in 200 mg (51%) of the title compound as a brown solid. MS-ESI: 231 (M+1).

Scheme 115: Intermediate 222 2,2,2-Trichloroethyl (2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate Step 1: (2-(trifluoromethyl) 2,2,2-Trichloroethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[002501] To a stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 2.48 mmol) in THF (30 ml) in a 100 mL round bottom flask under nitrogen, DIEA (639 mg, 4.96 mmol) was added at RT, followed by the addition of 2,2,2-trichloroethyl chloroformate (1.05 g, 4.96 mmol) per drip at RT. The resulting solution was stirred overnight at RT. The reaction solution was quenched with H2O (10 ml). The mixture was extracted with 3x50 ml of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 633 mg (68%) of the title compound as a yellow-brown solid. MS-ESI: 376/378/380 (M+1).

Table 48. The Intermediates in the Table below were prepared using similar procedures to convert compound 354 to Intermediate 222 shown in Scheme 115 from suitable starting materials.

Exact Mass Intermediate Structure IUPAC Name Daily No. [MH]-(2-(Difluoromethyl)-6,7-di- Intermehydro-5H-Daily cyclopenta[b]pyridin-4-358/360/362 223 yl)carbamate 2,2,2-Trichloroethyl (3-ethyl-2-(2,2,2-Intermetrifluoroethyl)-6,7-dihydrodaily 5H-cyclopenta[b]pyridin-419/421/423 224 2,2,2-Trichloroethyl (2-(1-fluorocyclopropyl)-Interme-3-methyl-6,7-dihydro-5H-daily cyclopenta[b]pyridin-4-4-yl)carbamate 381/383 /385 225 2,2,2-Trichloroethyl(3-cyclopropyl-2-(2,2,2-Intermetrifluoroethyl)-6,7-dihydrodaily 5H-cyclopenta[b]pyridin-yl)carbamate 431/433/435 226 2,2,2-Trichloroethyl 4-yl)carbamate (3-Cyclopropyl-2-(trifluoromethyl)-6,7-di-Intermehydro-5H-daily 417/419/421 cyclopenta[ b]pyridin-4-yl) 2,2,2-trichloroethyl carbamate

Interme- Exact Mass Structure IUPAC Name Daily No. [MH]-(3,5-Dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-Intermethyl)carbamate of 2,2,2-daily trichloroethyl and (3,6-405/407/409,228 dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate of 2,2,2-Trichloroethyl (2-Methyl-3-(trifluoromethyl)-6,7-di-Intermehydro-5H-daily 391/393/395 cyclopenta[b]pyridin-4-yl)carbamate of 2 ,2,2-Trichloroethyl (3-oxo-1,2,3,5,6,7-hexa-Intermehydrodicyclopendicum ta[b,e]pyridin-8-363/365/367 230yl)carbamate of 2,2,2-Trichloroethyl (2-methyl-3-phenyl-6,7-di-Intermehydro-5H-daily cyclopenta[b]pyridin-4-399/401/403 231 yl)carbamate of 2,2 ,2-Trichloroethyl (3-methyl-2-(2,2,2-Intermetrifluoroethyl)-6,7-dihydrodaily 5H-cyclopenta[b]pyridin-405/407/409 232 4-yl) 2,2,2-trichloroethyl carbamate

[002502] Schemes of Sulfonimidamide and Amino Pyridine Intermediates: Schemes 116 to 122 illustrate the preparation of sulfonimidamide and amino pyridine intermediates. Scheme 116: Intermediate 233 N'-(tert-butyldimethylsilyl)-2-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disyladecan-5-yl )thiazol-5-sulfonimidamide Step 1: 2-((tert-butyldimethylsilyl)oxy)-1-(thiazol-2-yl)ethan-1-ol

[002503] To a stirred solution of 2-bromothiazole (10.0 g, 61.3 mmol) in THF (120 ml) under nitrogen was added n-BuLi (2.5 M in hexane, 36.8 ml, 92, 0 mmol) by dripping at -78°C. The resulting solution was stirred at -78 °C for 20 min, then to the above solution was added 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (16.0 g, 92.0 mmol) in THF (10 ml) by dripping at -78°C. The resulting solution was stirred for 2 h at -50 °C. The reaction was quenched with water (50 ml). The resulting mixture was concentrated to remove THF under vacuum. The aqueous phase was extracted with EtOAc (3x100 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:9). This resulted in 8.1 g (51.0%) of the title compound as a yellow oil. MS-ESI: 260 (M+1). Step 2: 2-(2,2,3,3,8,8,9,9-Octamethyl-4,7-dioxa-3,8-disyladecan-5-yl)thiazole

[002504] To a stirred solution of 2-((tert-butyldimethylsilyl)oxy)-1-(thiazol-2-yl)ethan-1-ol (8.0 g, 30.9 mmol) in THF (150 ml) under nitrogen, NaH (60% by weight, 3.09 g, 77.3 mmol) was added in portions at 0 °C. The resulting solution was stirred for 10 min at 0 °C. Then, to the above solution, TBSCl (18.6 g, 124 mmol) in THF (15 ml) was added dropwise at 0 °C. The resulting solution was stirred for 16 h at RT. The reaction was quenched with water (100 ml), the resulting mixture was concentrated to remove THF under vacuum. The aqueous phase was extracted with EtOAc (3x100 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (4:96). This resulted in 8 g (69.3%) of the title compound as a yellow oil. MS-ESI: 374 (M+1).

[002505] Steps 3 to 6 used similar procedures to convert compound 485 to Intermediate 203 shown in Scheme 98 to provide Intermediate 233 from compound 561. MS-ESI: 566 (M+1). Scheme 117: Intermediate 234

5-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-N,N-dimethylthiazole-2-carboxamide Step 1: Thiazole-2-carbonyl chloride

[002506] To a stirred solution of thiazole-2-carboxylic acid (2.0 g, 15.5 mmol) in DCM (100 mL), DMF (0.095 mL, 1.24 mmol) was added followed by oxalyl chloride ( 5.91 g, 46.5 mmol) by dripping at 0 °C. The reaction mixture was stirred for 1 h at RT. The resulting mixture was concentrated in vacuo. This resulted in 2.4 g (crude product) of the title compound as a yellow solid, which was used in the next step without further purification. Step 2: N,N-dimethylthiazole-2-carboxamide

[002507] To a stirred solution of dimethylamine (2M in THF, 38.8 ml, 77.5 mmol), was added thiazole-2-carbonyl chloride (2.30 g, crude product from last step) in THF ( 60 ml) by dripping at 0°C. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with water (100 ml) and extracted with EtOAc (3 x 100 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 2.18 g (90% over 2 steps) of the title compound as a yellow oil. MS-ESI: 157 (M+1).

[002508] Steps 3 to 6 used similar procedures to convert compound 485 to Intermediate 203 shown in Scheme 98 to provide Intermediate 234 from compound 567. MS-ESI: 349 (M+1).

Scheme 118: Intermediate 235 tert-Butyl (amino(1-ethyl-4-fluoro-1H-pyrazol-5-yl)(oxo)-16-sulfanoylidene)carbamate Step 1: 1-ethyl-4-fluoro-1H- pyrazole

[002509] To a stirred solution of 4-fluoro-1H-pyrazole (1.72 g, 20.0 mmol) in DMF (15 mL) under nitrogen was added Cs2CO3 (13.0 g, 40.0 mmol) and ethyl iodide (9.36 g, 60.0 mmol) at RT. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with water (20 ml) and extracted with ether (2 x 50 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 2.0 g (87.7%) of the title compound as a brown oil. MS-ESI: 115 (M+1). Step 2: 1-Ethyl-4-fluoro-1H-pyrazol-5-sulfinamide

[002510] To a stirred solution of 1-ethyl-4-fluoro-1H-pyrazole (1.5 g, 13.2 mmol) in THF (50 mL) under nitrogen was added n-BuLi (2.5 M in hexane (2S ,3aS,8aR)-3-tosyl-3,3a,8,8a-tetra-

hydroindeno[1,2-d][1,2,3]oxathiazole (4.82 g, 13.8 mmol) in THF (15 mL) dripped at -78 °C. The resulting solution was stirred for 3 h at -78 °C. To the above mixture, KHMDS (1M in THF, 26.3 mL, 26.3 mmol) was added dropwise at -78 °C. The resulting solution was stirred for 1 h at -78 °C. The solution was slowly warmed at RT and stirred for a further 1 h at RT. The reaction mixture was quenched with MeOH (50 ml) and concentrated in vacuo. The residue was diluted with water (100 ml) and extracted with EtOAc (2 x 100 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with PE/EtOAc (1:1). This resulted in 790 mg (ee value = 0) (33.8%) of the title compound as an orange solid. MS-ESI: 178 (M+1). The regiochemistry of compound 572 was confirmed by NOESY. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 4.4 Hz, 1H), 6.91 (s, 2H), 4.35-4.16 (m, 2H), 1 .33 (t, J = 7.2, Hz, 3H). NOESY: NH2 at 6.91 (s, 2H) has correlations with N-Et's CH2 at 4.35-4.16 (m, 2H) and CH3 at 1.33 (t, J = 7.2, Hz , 3H). Step 3: tert-butyl ((1-ethyl-4-fluoro-1H-pyrazol-5-yl)sulfinyl)carbamate

[002511] To a stirred solution of 1-ethyl-4-fluoro-1H-pyrazol-5-sulfinamide (696 mg, 3.93 mmol) in THF (25 mL) under nitrogen was added t-BuOLi (1 M in THF, 7.86 ml, 7.86 mmol) by dripping at 0°C. The resulting mixture was stirred for 1 h at 0 °C. To the above mixture, di-tert-butyl dicarbonate (3.42 g, 15.7 mmol) in THF (10 ml) was added dropwise at 0 °C. The resulting mixture was stirred for 3 h at 0 °C and then quenched with MeOH (10 ml) and concentrated in vacuo. The residue was diluted with water (30 ml) and extracted with EtOAc (2 x 30 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with PE/EtOAc (5:1). This results in

tou in 717 mg (65.8%) of the title compound as a light yellow oil. MS-ESI: 278 (M+1). Step 4: tert-Butyl (amino(1-ethyl-4-fluoro-1H-pyrazol-5-yl)(oxo)-16-sulfanoylidene)carbamate

[002512] To a stirred solution of tert-butyl ((1-ethyl-4-fluoro-1H-pyrazol-5-yl)sulfinyl)carbamate (717 mg, 2.59 mmol) in ACN (25 ml) was bubble of NH3 (g) was introduced at 0 °C for 10 min. Then, to the above solution, NCS (3.45 g, 25.9 mmol) was added in portions at 0 °C. The resulting solution was stirred for 3 h at 35 °C in an oil bath. The residue was quenched with water (100 ml) and extracted with EtOAc (3 x 150 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with PE/EtOAc (3:2). The product was further purified by prep. with the following conditions: Column XSelect CSH Prep C18 OBD, 19*250 mm, 5 µm Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 30% B to 53% B for 7 min; 254/210 nm. This resulted in 163 mg (21.6%) of the title compound as a white solid. MS-ESI: 293 (M+1). Scheme 119:

Intermediate 236 3,5-Dimethyl-2,6-bis(trifluoromethyl)pyridin-4-amine Step 1: 1,1,1,7,7,7-Hexafluoroheptane-2,4,6-trione

[002513] To a stirred mixture of LiH (1.51 g, 189 mmol) in DME (100 mL) under nitrogen was added ethyl 2,2,2-trifluoroacetate (26.9 g, 189 mmol) and acetone ( 5.0 g, 86.2 mmol) by dripping at 0 °C. The resulting mixture was stirred for 16 h at 80 °C under nitrogen. The mixture was allowed to cool to RT, and 50 ml of DME solvent was evaporated under vacuum. The residue was quenched with H 2 SO 4 (15% by weight in water, 50 ml) dropwise at 0°C. The aqueous layer was extracted with DCM (3x50ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in toluene (50 ml) and heated to reflux with a Dean-Stark collector for 4 h. After all the water had been separated, the resulting mixture was cooled and evaporated in vacuo to give the title compound (26 g, crude product) as a red solid. MS-ESI: 249 (M-1) Step 2: 2,6-Bis(trifluoromethyl)pyridin-4-amine

[002514] To a stirred solution of 1,1,1,7,7,7-hexafluoroheptane-2,4,6-trione (14.7 g of crude product from the last step) in EtOH (300 ml), NH4OAc (36.3 g, 471 mmol) was added in portions at RT. The resulting mixture was heated at reflux with stirring for 16 h under nitrogen. The mixture was allowed to cool to RT. The reaction was quenched with water (50 ml) and concentrated to remove EtOH under vacuum. The aqueous layer was extracted with EtOAc (3x30ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with PE/EtOAc (10:1) to afford the title compound (9.63 g, 85.9% over two steps) as a yellow solid. MS-ESI: 229 (M-1). Step 3: 3,5-Dibromo-2,6-bis(trifluoromethyl)pyridin-4-amine

[002515] To a stirred solution of 2,6-bis(trifluoromethyl)pyridin-4-amine (4.80 g, 20.9 mmol) in ACN (150 ml) under nitrogen was added NBS (18.7 g, 105 mmol) in portions at 0°C. The resulting mixture was stirred for 16 h at 60 °C. The reaction was quenched with saturated aqueous Na2S2O3 (50 ml). The aqueous layer was extracted with EtOAc (3x50ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with PE/EtOAc (20:1) to provide the title compound (5.69 g, 70.2%) as a yellow solid. MS-ESI: 385/387/389 (M-1). Step 4: 3,5-Dimethyl-2,6-bis(trifluoromethyl)pyridin-4-amine

[002516] To a stirred mixture of 3,5-dibromo-2,6-bis(trifluoromethyl)pyridin-4-amine (5.50 g, 14.2 mmol) in dioxane (125 ml) and H 2 O (12.5 ml) in a sealed tube under nitrogen, 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50% by weight in THF, 17.9 g, 71.0 mmol), Pd(dppf)Cl2 (1.04 g, 1.42 mmol) and Cs2CO3 (13.9 g, 42.6 mmol) in portions at RT. The resulting mixture was stirred for 16 h at 90 °C. The mixture was allowed to cool to RT and then diluted with saturated aqueous NaCl (100 ml) and extracted with EtOAc (3x100 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with PE/EtOAc (10:1) to afford the title compound (3.35 g, 91.3%) as a pale yellow solid. MS-ESI: 259 (M+1).

Scheme 120: Intermediate 237 N'-(tert-butyldimethylsilyl)-4-fluoro-1-phenyl-1H-pyrazol-3-sulfonimidamide Step 1: N,N-dibenzyl-4-fluoro-1-phenyl-1H-pyrazol- 3-sulfonamide

[002517] To a stirred solution of N,N-dibenzyl-4-fluoro-1H-pyrazol-3-sulfonamide (4.0 g, 11.6 mmol) in DMF (120 ml), phenylboronic acid (4. 24 g, 34.8 mmol), pyridine (2.75 g, 34.7 mmol) and Cu 2 O (1.66 g, 44.6 mmol) in portions at RT. The resulting mixture was stirred for 16 h at 70 °C under air. Solids were removed by filtration. The resulting solution was diluted with 250 ml of water and extracted with 4x150 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from silica gel with EtOAc/PE (1:15). This resulted in 3.31 g (67.8%) of the title compound as a white solid. LCMS-ESI: 422 (M+1).

[002518] Steps 2 to 5 used similar procedures to convert compound 458A to Intermediate 197 shown in Scheme 93 to provide Intermediate 237 from compound 578. MS-ESI: 355 (M+1). Scheme 121:

Intermediate 238 3-(4-Fluorophenyl)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 3-(4-Fluorophenyl)-2-(trifluoromethyl) )-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002519] To a stirred solution of 3-bromo-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 1.78 mmol) in dioxane (10 ml) and H2O (1.0 ml) under nitrogen, (4-fluorophenyl)boronic acid (498 mg, 3.56 mmol), K3PO4 (1132 mg, 5.34 mmol) and Pd(dtbpf)Cl2 (116 mg, 0.178 mmol) in portions at RT. The reaction mixture was stirred for 16 h at 100 °C. The reaction was diluted with 10 ml of water and extracted with 3x10 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:2). This resulted in 230 mg (43.5%) of the title compound as a yellow solid. MS-ESI: 297 (M+1). Table 60 The Intermediates in the Table below were prepared using similar procedures to convert compound 355 to Intermediate 238 shown in Scheme 121 from suitable reagents.

Mass Intermediate No. Structure Exact IUPAC Name [M+H]+ 3-phenyl-2-(trifluoromethyl)-6,7- Intermediate dihydro-5H- 279 239 cyclopenta[b]pyridin-4-amine 3-cyclopropyl-2 - Intermediate (trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine 3-(2-Fluorophenyl)-2- Intermediate (trifluoromethyl)-6,7-dihydro- 297 241 5H-cyclopenta[b]pyridin-4-amine 3-(3-Fluorophenyl)-2-Intermediate (trifluoromethyl)-6,7-dihydro-297 242 5H-cyclopenta[b]pyridin-4-amine Scheme 122: Intermediate 243 3-Phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002520] To a stirred solution of 2-aminocyclopent-1-ene-1-carbonitrile (20 g, 185 mmol) in DCE (400 mL) under nitrogen was added 2-phenylacetaldehyde (44.4 g, 370 mmol) and BF3.Et2O (47% by weight, 25 g, 370 mmol) dripped at 0°C.

The resulting solution was stirred for 16 h at 110 °C.

The resulting mixture was concentrated in vacuo.

The resulting residue was diluted with 500 ml of water, then extracted with 3x500 ml of EtOAc.

The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo.

The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 250 mg (0.64%) of the title compound as a yellow solid.

MS-ESI: 211 (M+1). Table 61. The Intermediates in the following table were prepared using similar procedures to convert compound 451 to Intermediate 197 shown in Scheme 93. Interme- Mass Exa- Structure IUPAC Name Daily No. ta [MH]- N'-( tert -butyldimethylsilyl)- Interme-4-fluoro-1-isopropyl-1H- daily 321 pyrazol-3- 244 sulfonimidamide Table 62 The Intermediates in the following table were prepared using the similar procedures to convert Intermediate 45 to Intermediate 161 shown in Scheme 82 from Intermediate 45 and (S)-(+)-Mandelic acid.

Interme- Exa Mass- Structure IUPAC name daily no. ta [M+H]+

(S)-3-Methyl-1,2,3,5,6,7-Intermexadaily 189 hydrodicyclopent-245 ta[b,e]pyridin-8-amine

Table 63 The Intermediates in the Table below were prepared using similar procedures to convert compound 354 to Intermediate 222 shown in Scheme 115 from suitable starting materials.

Interme- Mass Exa- Structure IUPAC name daily no. [MH]-(3-(4-Fluorophenyl)-2-(trifluoromethyl)-6,7-di-Intermehydro-5H-471/473/47 daily cyclopenta[ 2,2,2-Trichloroethyl (3-Phenyl-2-(trifluoromethyl)-6,7-di-Intermehydro-5H-453/455/45 daily cyclopenta[ b]pyridin-4-5 246yl)carbamate 2,2,2-Trichloroethyl (3-Cyclopropyl-2-(trifluoromethyl)-6,7-di-Intermehydro-5H-417/419/42 daily cyclopenta[ b]pyridin-4-247yl)carbamate 2,2,2-Trichloroethyl (3-(3-Fluorophenyl)-2-(trifluoromethyl)-6,7-di-Intermehydro-5H-471/473 b]pyridin-4-1248yl)carbamate 47 daily 2,2,2-Trichloroethyl (3-(2-Fluorophenyl)-2-(trifluoromethyl)-6,7-di-Intermehydro-5H-cyclopenta[b]pyridin-4- 471/473/47 daily 2,2,2-trichloroethyl cyclopenta[b]pyridin-4-5 250yl)carbamate

2,2,2-9 251 Trichloroethyl (3-Phenyl-6,7-dihydro-5H-Daily Intermecyclopenta[b]pyridin-4-385/387/38 yl)carbamate

Interme- Exa Mass- Structure IUPAC name daily no. ta [MH]-(S)-(3-Methyl-1,2,3,5,6,7-hexa- Intermehydrodicyclopen- 363/365/36 daily ta[ 2,2,2-Trichloroethyl b,e]pyridin-8-252yl)carbamate Scheme 123: Intermediate 253 N'-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl) thiophene-2-sulfonimidamide Step 1: N-(tert-butyl)-5-chlorothiophene-2-sulfonamide

[002521] To a stirred solution of tBuNH2 (20.2 g, 276 mmol) in DCM (180 mL) under nitrogen was added TEA (42.0 g, 415 mmol), followed by the addition of 5-chlorothiophene chloride. 2-sulfonyl (10.0 g, 46.3 mmol) in DCM (20 ml) dripped at 0 °C. The resulting solution was stirred for 16 h at 35 °C. The reaction was quenched with water/ice (200 ml) and extracted with DCM (2 x 200 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated.

under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 11.0 g (93.9%) of the title compound as a yellow solid. MS-ESI: 252/254 (M-1). 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 7.21 (d, J = 4.1 Hz, 1H ), 1.17 (s, 9H). Step 2: N-(tert-butyl)-5-chloro-3-fluorothiophene-2-sulfonamide

[002522] To a stirred solution of N-(tert-butyl)-5-chlorothiophene-2-sulfonamide (11.0 g, 43.5 mmol) in THF (200 mL) under nitrogen was added n-BuLi (2 .5M in hexane, 52.4 ml, 131 mmol) by drip at -78 °C. The resulting solution was stirred at -78 °C for 1 h. To the above solution, NFSI (41.6 g, 131 mmol) in THF (100 ml) was added dropwise at -78 °C. The resulting solution was slowly warmed to RT and stirred at RT for a further 1 h. The reaction mixture was then quenched with water/ice (250 ml) and extracted with EtOAc (3x300 ml). The combined organic layers were anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:20). This resulted in 6.2 g (43.3%) of the title compound as a yellow solid. MS-ESI: 270/272 (M-1). Step 3: N-(tert-butyl)-5-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[002523] To a stirred solution of N-(tert-butyl)-5-chloro-3-fluorothiophene-2-sulfonamide (6.2 g, 22.8 mmol) in THF (200 ml) under nitrogen was added n -BuLi (2.5M in hexane, 91.2 ml, 228 mmol) dripped at -78°C. The resulting solution was stirred for 50 min at -78 °C. Thereto, acetone (53.0 g, 913 mmol) is added dropwise with stirring at -78°C. The resulting solution was stirred for a further 1.5 h at -60 °C. The reaction was then quenched with water/ice (200 ml) and extracted with EtOAc (2x300 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:5). This resulted in 4.4 g (65.4%) of the title compound as a yellow oil. MS-ESI: 328/330 (M-1). Step 4: N-(tert-butyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[002524] To a stirred solution of N-(tert-butyl)-5-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (4.3 g, 13.1 mmol ) in MeOH (80 ml) under nitrogen, Pd/C (10% by weight, 470 mg) was added in portions at RT. The flask was evacuated and refilled with hydrogen three times. The resulting mixture was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered, and the filtrate was concentrated in vacuo. This resulted in 3.88 g (crude product) of the title compound as a white solid. MS-ESI: 294 (M-1). Step 5: 3-Fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[002525] To a stirred solution of N-(tert-butyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (3.88 g, 13.1 mmol) in DCM ( 78 ml) under nitrogen, BCl 3 (1M in DCM, 39 ml, 39 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched with water/ice (80 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (2:3). This resulted in 1.9 g (60.7% over 2 steps) of the title compound as a yellow oil. MS-ESI: 238 (M-1). Step 6: N'-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[002526] To a stirred solution of 3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (1.89 g, 7.91 mmol) in THF (40 ml) under nitrogen, NaH (60% by weight, 630 mg, 15.9 mmol) was added in portions at 0 °C, followed by the addition of TBSCl (2.39 g, 15.9 mmol) in THF (5 mL) by drip. with stirring at 0°C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with water/ice (50 ml). The resulting solution was extracted with EtOAc (2x50 ml). The organic layers were combined and dried over anhydrous Na2SO4. The resulting mixture was concentrated in vacuo. The residue was eluted from a silica gel column with ethyl EtOAc/PE (1:3). This resulted in 2.1 g (75.2%) of the title compound as a white solid. MS-ESI: 352 (M-1). 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.56 (d, J = 5.1 Hz, 1H), 5.38 (s, 1H), 1.43 (s , 6H), 0.89 (s, 9H), 0.16 (s, 6H). Step 7: N'-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

[002527] To a stirred solution of PPh3Cl2 (1.41 g, 4.24 mmol) in CHCl3 (15 mL) under nitrogen, DIEA (1.83 g, 14.1 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 15 min at 0 °C. To the above solution was added N-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazol-5-sulfonamide (1.0 g, 2.83 mmol) in CHCl 3 (10 ml) by dripping at 0°C. The resulting solution was stirred for 2 h at 0 °C. NH3 (g) was bubbled into the reaction solution for 10 min at 0 °C. Then, the solution was stirred for a further 30 min at RT. The solids were removed by filtration, the filtrate was diluted with water (20 ml). The resulting solution was extracted with DCM (3x20 ml). The organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 800 mg (80.1%) of the title compound as an off-white solid. MS-ESI: 351 (M-1).

Scheme 124: Intermediate 254 N'-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazole-5-sulfonimidamide Step 1: 2-(Difluoromethyl)thiazole

[002528] To a stirred solution of thiazole-2-carbaldehyde (10 g, 88.5 mmol) in DCM (150 ml) under a nitrogen atmosphere was added DAST (28.6 g, 178 mmol) by droplet at -78°C. °C The resulting mixture was stirred for 16 h at RT. The reaction was quenched with 100 ml of water/ice at 0°C. The mixture was neutralized to pH=8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with DCM (2x100ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo below 5°C. This resulted in the title compound (5.8 g, 48.5%) as a yellow oil which was used for the next step without further purification. 1H NMR (400 MHz, CDCl 3 ) δ 7.94 (dt, J = 3.0, 1.4 Hz, 1H), 7.58 (d, J = 3.1 Hz, 1H), 6.91 (t , J = 54.8 Hz, 1H). Step 2: Lithium 2-(difluoromethyl)thiazole-5-sulfinate

[002529] To a stirred solution of 2-(difluoromethyl)thiazole (5.8 g, 43.0 mmol) in THF (50 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 21.0 ml, 52.5 mmol) by dripping at -78°C. The resulting solution was stirred for 20 min at -78 °C. To the above solution, it was introduced

of SO2 bubbled at -78 °C for 5 min. The resulting mixture was stirred for 2 h at RT and concentrated in vacuo. This resulted in 16.5 g (crude product) of the title compound as a dark yellow solid, which was used in the next step without further purification. MS-ESI: 198 (M-1). Step 3: 2-(Difluoromethyl)thiazole-5-sulfonamide

[002530] To a stirred solution of lithium 2-(difluoromethyl)thiazole-5-sulfinate (16.5 g, crude product from the last step) in ACN (50 ml), was added NCS (17.1 g, 128 mmol) in portions at 0 °C. The resulting solution was stirred for 2 h at RT. To the above solution, NH3 was bubbled at 0 °C for 10 min. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 2.87 g (15.2% over two steps) of the title compound as a yellow solid. MS-ESI: 213 (M-1). 1H NMR (400 MHz, CDCl 3 ) δ 8.33 (t, J = 1.5 Hz, 1H), 6.87 (t, J = 54.3 Hz, 1H), 5.55 (s, 2H). Step 4: N-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazol-5-sulfonamide

[002531] To a stirred solution of 2-(difluoromethyl)thiazol-5-sulfonamide (2.87 g, 13.4 mmol) in THF (50 mL) under nitrogen was added NaH (60 wt%, 2.05 g, 51.2 mmol) in portions at 0 °C, followed by the addition of TBSCl (4.59 g, 30.6 mmol) in THF (5 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with 50 ml of water/ice. The resulting solution was extracted with EtOAc (2x50 ml). The organic layers were combined and dried over anhydrous Na2SO4. The resulting mixture was concentrated in vacuo. The residue was eluted from a silica gel column with ethyl EtOAc/PE (1:4). This resulted in 2.48 g (56.4%) of the title compound as a yellow solid. MS-ESI: 327 (M-1).

Step 5: N'-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazol-5-sulfonimidamide

[002532] To a stirred solution of PPh3Cl2 (2.43 g, 7.31 mmol) in CHCl3 (30 mL) under nitrogen, DIEA (2.40 g, 18.6 mmol) was added dropwise at 0 °C. The resulting solution was stirred for 15 min at 0 °C. To the above solution, N-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazol-5-sulfonamide (1.20 g, 3.66 mmol) in CHCl 3 was added. (5 ml) by dripping at 0°C. The resulting solution was stirred for 2 h at 0 °C. NH3 (g) was bubbled into the reaction solution for 15 min at 0 °C. Then, the solution was stirred for a further 2 h at RT. The solids were removed by filtration, the filtrate was diluted with water (20 ml). The resulting solution was extracted with DCM (3x20 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 670 mg (56.0%) of the title compound as a yellow oil. MS-ESI: 328 (M+1). Scheme 125:

Intermediate 255 N'-(tert-butyldimethylsilyl)-1-(1,1-difluoroethyl)-4-fluoro-1H-pyrazol-3-sulfonimidamide Step 1: 4-Fluoro-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazole

[002533] To a stirred solution of 4-fluoro-1H-pyrazole (5.00 g, 58.1 mmol) in 3,4-dihydro-2H-pyran (9.77 g, 116 mmol) under nitrogen, a catalytic amount of TFA (260 mg, 2.32 mmol) was added. The resulting solution was stirred for 16 h at 100 °C. The reaction was then quenched with 200 mg of NaH (60% by weight) at 0°C. The resulting solution was diluted with water (100 ml). The resulting solution was extracted with EtOAc (3x100 ml). The organic layers were combined and dried over anhydrous Na2SO4. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. This resulted in 12.0 g (crude product) of the title compound as a light brown oil. MS-ESI: 171 (M+1). Step 2: Lithium 4-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-sulfinate

[002534] To a stirred solution of 4-fluoro-1-(oxan-2-yl)pyrazole (12.0 g, crude product from last step) in THF (250 ml), was added n-BuLi (2.5 M in hexane, 20.0 ml, 50 mmol) by droplet at -78°C. The resulting solution was stirred for 40 min at -78 °C. To the above solution, SO2 (g) was bubbled at -78 °C for 5 min. Then, the temperature was warmed up to RT. The resulting solution was stirred for a further 1 h at RT. The resulting mixture was concentrated in vacuo. This resulted in 28.0 g (crude product) of the title compound as a light yellow semi-solid. MS-ESI: 233 (M-1). Step 3: N-(tert-butyl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-

pyrazole-5-sulfonamide

[002535] To a solution of lithium 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-sulfinate (28.0 g, crude product from the last step) in ACN (200 ml) was added NCS (19.9 g, 149 mmol) in ACN (50 ml) dropwise at 0 °C. The resulting solution was stirred for 1 h at RT. To the above reaction mixture, tBuNH2 (49.8 g, 683 mmol) was added dropwise with stirring at 0 °C. The resulting solution was stirred for a further 30 min at RT. The resulting mixture was concentrated in vacuo and diluted with 200 ml of water. The resulting solution was extracted with 3x150 ml of EtOAc, and the organic layers were combined. The residue after evaporation was purified by preparatory TLC with EtOAc/PE (1:4). This resulted in 13.3 g (75.0% over three steps) of the title compound as a yellow solid. MS-ESI: 304 (M-1). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 4.6 Hz, 1H), 5.90 (dd, J = 8.6, 2.9 Hz, 1H), 5.17 (s , 1H), 3.98-3.86 (m, 1H), 3.80-3.68 (m, 1H), 2.48-2.32 (m, 1H), 2.21-2.02 (m, 2H), 1.85-1.55 (m, 3H), 1.31 (s, 9H). Step 4: N-(tert-butyl)-4-fluoro-1H-pyrazol-5-sulfonamide

[002536] To a solution of N-(tert-butyl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-sulfonamide (13.3 g, 43. 6 mmol) in MeOH (220 ml), HCl (conc., 20 ml) was added dropwise at 0 °C. The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated in vacuo. This resulted in 9.7 g (crude product) of the title compound as a yellowish green solid. MS-ESI: 222 (M+1). Step 5: 1-(2-Bromo-1,1-difluoroethyl)-N-(tert-butyl)-4-fluoro-1H-pyrazol-3-sulfonamide

[002537] To a solution of N-(tert-butyl)-4-fluoro-1H-pyrazol-5-sulfonamide (9.70 g, 43.8 mmol) in THF (200 ml), was added DBU (33, 4 g, 219 mmol) at -20°C. The resulting solution was stirred for 5 min at -20 °C. Then, 2-bromo-1,1-difluoroethene was bubbled into this reaction mixture at -20 °C for 10 min. The resulting solution was stirred for

1 h at -20°C. The resulting mixture was concentrated and diluted with 150 ml of water. The resulting solution was extracted with EtOAc (3x100 ml). The organic layers were combined and dried over anhydrous Na2SO4. The residue was purified by preparatory TLC with EtOAc/PE (1:2). This resulted in 8.5 g (53.7% over 2 steps) of the title compound as a yellow solid. MS-ESI: 364/366 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 4.5 Hz, 1H), 8.21 (s, 1H), 4.58 (t, J = 12.1 Hz, 2H ), 1.19 (s, 9H). NOESY: Ar-H at 8.80 (d, J = 4.5 Hz, 1H) correlated with CH 2 at 4.58 (t, J = 12.1 Hz, 2H).

[002538] This also resulted in 2.0 g (13.4%) of by-product (E)-1-(2-bromo-1-fluorovinyl)-N-(tert-butyl)-4-fluoro-1H-pyrazole -3-sulfonamide (599BP") as a yellow solid that eluted after 599". MS-ESI: 344/346 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 5.0 Hz, 1H), 6.27 (d, J = 5.3 Hz, 1H), 5.00 (sl, 1H), 1.36 (s, 9H). Step 6: N-(tert-butyl)-1-(1,1-difluoroethyl)-4-fluoro-1H-pyrazol-3-sulfonamide

[002539] To a stirred solution of 1-(2-bromo-1,1-difluoroethyl)-N-tert-butyl-4-fluoropyrazol-3-sulfonamide (8.0 g, 22.0 mmol) in EtOH (250 ml) in a stainless steel pressure reactor under nitrogen, Pd/C (10% by weight, 3.50 g) and AcOH (0.5 ml) were added. The mixture was stirred at 100 °C for 16 h under hydrogen (10 atm), filtered through a Celite filter and concentrated in vacuo. The residue was purified by preparatory TLC (EA/PE 1:1) to provide 5.0 g of the title compound (79.7%) as a pale yellow solid. MS-ESI: 286 (M+1). Step 7: 1-(1,1-Difluoroethyl)-4-fluoro-1H-pyrazol-3-sulfonamide

[002540] N-tert-butyl-1-(1,1-difluoroethyl)-4-fluoropyrazol-3-sulfonamide (5.0 g, 17.5 mmol) was added to HCl (conc. 50 ml) in portions with stirring at 0°C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 3.90 g (97.3%) of the title compound as a yellow solid. MS-ESI: 230 (M+1).

[002541] Steps 8 through 9 used similar procedures to convert compound 588" to Intermediate 253 shown in Scheme 123 to provide Intermediate 255 from compound 601". MS-ESI: 343 (M+1). Table 63A. The Intermediates in the Table below were prepared using similar procedures to convert compound 355" to Intermediate 238 shown in Scheme 121 from suitable reagents. Interme- Exact Mass Structure IUPAC Name Daily No. [M+H]+ 3-(3,4-Difluorophenyl)-Interme-2-(trifluoromethyl)-6,7-daily dihydro-5H- 315 256 cyclopenta[b]pyridin-4-amine Scheme 126: Intermediate 257 3-(3, 4-Difluorophenyl)-4-isocyanato-2-(trifluoromethyl)-6,7-dihydro-5H-

cyclopenta[b]pyridine

[002542] To a solution of 3-(3,4-difluorophenyl)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (200 mg, 0.637 mmol) in THF (4 ml) under nitrogen, TEA (129 mg, 1.28 mmol) and BTC (151 mg, 0.508 mmol) were added at 0 °C. The resulting solution was stirred for 2 h at 70 °C. This resulted in the title compound in a brown solution which was used for the next step directly. Scheme 127: Intermediate 258 N'-(tert-butyldimethylsilyl)-2-(2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6 -yl)thiazol-5-sulfonimidamide Step 1: Diethyl 2-(thiazol-2-yl)malonate

[002543] To a stirred solution of ethyl 2-(thiazol-2-yl)acetate (2.0 g, 11.7 mmol) in THF (20 ml) under nitrogen was added NaH (60% by weight of dispersion in mineral oil, 1.0 g, 25.0 mmol) in portions at 0 °C. The resulting solution was stirred for 30 min at 0 °C. Then, diethyl carbonate (23.0 g, 195 mmol) was added dropwise to the above solution. The resulting solution was stirred for 8 h at 65 °C. The reaction was then quenched with 30 ml of water, then ex-

extracted with 3x50 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was eluted from silica gel with EtOAc/PE (1/2). This resulted in 2.44 g (85.8%) of the title compound as a pale yellow solid. MS-ESI: 242 (M-1). Step 2: Diethyl 2-methyl-2-(thiazol-2-yl)malonate

[002544] To a stirred solution of diethyl 2-(thiazol-2-yl)malonate (2.0 g, 8.22 mmol) in THF (30 ml), was added DBU (2.50 g, 16.4 mmol) at 0°C. Then, MeI (4.67 g, 32.9 mmol) was added dropwise to the above solution. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 20 ml of water/ice and then extracted with 3x50 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by preparatory TLC with EtOAc/PE (1/2). This resulted in 1.3 g (61.5%) of the title compound as a pale yellow oil. MS-ESI: 258 (M+1). Step 3: 2-Methyl-2-(thiazol-2-yl)propane-1,3-diol

[002545] To a stirred solution of diethyl 2-methyl-2-(thiazol-2-yl)malonate (1.0 g, 3.89 mmol) in THF (30 ml) was added DIBAL-H (1 M in hexane, 7.82 ml, 7.82 mmol) by dripping at 0 °C for 5 min. The resulting solution was stirred for 24 h at RT. The reaction was then quenched with 10 ml of MeOH. The resulting mixture was concentrated in vacuo. The crude product was purified by reverse phase column with ACN/water (15/75). This resulted in 290 mg (43.1%) of the title compound as a pale yellow oil. MS-ESI: 174 (M+1). Step 4: 2-(2,2,3,3,6,9,9,10,10-Nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)thiazole

[002546] To a stirred solution of 2-methyl-2-(thiazol-2-yl)propane-1,3-diol (72.0 mg, 0.416 mmol) in THF (10 ml) under nitrogen was added NaH (60% by weight, 66.6 mg, 1.66 mmol) in portions at 0°C. The resulting solution was stirred for 30 min at 0 °C. Then, TBSCl (190 mg, 1.25 mmol) was added to the above solution at 0 °C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 10 ml of water/ice and extracted with 3x30 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated. This resulted in 300 mg (crude product) of the title compound as a pale yellow crude oil. MS-ESI: 402 (M+1).

[002547] Steps 5 through 8 used similar procedures to convert compound 485'' to Intermediate 203 shown in Scheme 98 to provide Intermediate 258 from compound 607''. MS-ESI: 594 (M+1) Scheme 128: Intermediate 259 N'-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)thiazol-5- sulfonimidamide Step 1: Ethyl 2-methyl-2-(thiazol-2-yl)propanoate

[002548] To a stirred solution of ethyl 2-(thiazol-2-yl)acetate (2.50 g, 14.6 mmol) in THF (30 ml) under nitrogen was added NaH (60% by weight, 1 .75 g, 43.8 mmol) in portions at 0 °C, followed by the dropwise addition of methyl iodide (20.7 g, 146 mmol) at 0 °C. The resulting solution was stirred for 16 h at RT. The reaction was quenched with water/ice (30 ml). The resulting mixture was extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (2x30 ml), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (10:1). This resulted in 1.4 g (48.2%) of the title compound as a yellow solid. MS-ESI: 200 (M+1). Step 2: 2-Methyl-2-(thiazol-2-yl)propan-1-ol

[002549] To a stirred solution of ethyl 2-methyl-2-(thiazol-2-yl)propanoate (1.30 g, 6.53 mmol) in THF (50 ml), was added NaBH4 (1.44 g , 39.1 mmol) in portions at 0°C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with water/ice (15 ml). The resulting solution was extracted with 3x50 ml of EtOAc. The combined organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 600 mg (58.5%) of the title compound as a yellow solid. MS-ESI: 158 (M+1).

[002550] Steps 3 to 7 used similar procedures to convert compound 606'' to Intermediate 258 shown in Scheme 127 to provide Intermediate 259 from compound 613''. MS-ESI: 464 (M+1). Scheme 129:

Intermediate 219 2-Methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine Step 1: 3-Iodo-2-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-amine

[002551] To a stirred solution of 2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (2.50 g, 16.9 mmol) in TFA (100 ml) at 0 °C, NIS (7.61 g, 33.8 mmol) was added in portions at 0 °C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated in vacuo and then diluted with 250 ml of water. The resulting solution was extracted with 2x300 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtO-Ac/PE (9:1). This resulted in 1.70 g (36.7%) of the title compound as a white solid. MS-ESI: 275 (M+1) Step 2: 2-Methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002552] To a stirred solution of 3-iodo-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 1.82 mmol) in DMF (10 ml) to a sealed tube under nitrogen, (1,10-phenanthroline)(trifluoromethyl)copper(I) (2.27 g, 7.28 mmol) was added. The resulting solution was stirred for 16 h at 80 °C. Solids were removed by filtration. The filtrate was purified by prep HPLC. using the following conditions: Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 um; Mobile Phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 21% B to 35% B over 10 min; 254 nm; Rt: 9.27 min. that re-

resulted in 140 mg (35.5%) of the title compound as a white solid. MS-ESI: 217 (M+1). Scheme 130: Intermediate 260 N'-(tert-butyldimethylsilyl)-1-cyclopropyl-4-fluoro-1H-pyrazol-3-sulfonimidamide Step 1: N-(tert-butyl)-1-cyclopropyl-4-fluoro-1H- pyrazole-3-sulfonamide

[002553] To a stirred solution of N-(tert-butyl)-4-fluoro-1H-pyrazol-3-sulfonamide (3.0 g, 13.6 mmol) in DMF (100 ml), cyclopropylboronic acid ( 3.51 g, 40.8 mmol) and Cu2O (1.93 g, 13.6 mmol) in portions at RT. To the above mixture, pyridine (3.22 g, 40.8 mmol) was added dropwise at RT. The resulting mixture was stirred for 16 h at 70 °C under air. The resulting solution was filtered, the filter cake was washed with EtOAc (50 ml). The wash and filtrate were diluted with water (100 ml) and then extracted with EtOAc (3x100 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:6). This resulted in the title compound (1.4 g, 39.5%)

as a yellow solid. MS-ESI: 262 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.7 Hz, 1H), 7.77 (s, 1H), 3.86-3.76 (m, 1H), 1 .15 (s, 9H), 1.09-0.96 (m, 4H). Ar-H at 8.14 (d, J = 4.7 Hz, 1H) has correlations with cyclopropyl CH2 at 1.09-0.96 (m, 4H) and CH at 3.86-3.76 (m , 1H) in NOESY. Step 2: 1-cyclopropyl-4-fluoro-1H-pyrazol-3-sulfonamide

[002554] To HCl (30 ml, conc.), N-(tert-butyl)-1-cyclopropyl-4-fluoro-1H-pyrazol-3-sulfonamide (1.40 g, 5.36 mmol) was added in portions to RT. The resulting solution was stirred for 1 h at RT. The resulting solution was concentrated in vacuo. This resulted in the title compound (1.1 g, crude product) as a brown solid. MS-ESI: 206 (M+1).

[002555] Steps 3 to 4 used similar procedures to convert compound 588'' to Intermediate 253 shown in Scheme 123 to provide Intermediate 260 from compound 619''. MS-ESI: 319 (M+1). Scheme 131: Intermediate 261 N'-(tert-butyldimethylsilyl)-2-(trifluoromethyl)thiazol-5-sulfonimidamide Step 1: Lithium 2-(trifluoromethyl)thiazol-5-sulfinate

[002556] To a stirred solution of 2-(trifluoromethyl)thiazole (500 mg,

3.27 mmol) in THF (10 ml) under nitrogen, n-BuLi (2.5 M in hexane, 3.3 ml, 8.17 mmol) was added dropwise at -78 °C. The resulting solution was stirred for 20 min at -78 °C. To the above solution, SO2 (g) was introduced bubbled at -78 °C for 5 min. The resulting mixture was stirred for 2 h at RT and concentrated in vacuo. This resulted in 1.5 g (crude product) of the title compound as a yellow solid, which was used in the next step without further purification. MS-ESI: 216 (M-1). Step 2: 2-(Trifluoromethyl)thiazole-5-sulfonamide

[002557] To a stirred solution of lithium 2-(trifluoromethyl)thiazole-5-sulfinate (1.5 g, crude product from the last step) in ACN (10 ml), was added NCS (4.38 g, 32.7 mmol) in portions at 0°C. The resulting solution was stirred for 2 h at RT. To the above solution, NH3 (g) was bubbled at 0 °C for 5 min. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated in vacuo. The mixture was dissolved in EtOAc (200ml) then washed with water (2x50ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparatory TLC with EtOAc/PE (1:1). This resulted in 160 mg (21.1% over two steps) of the title compound as a pale yellow solid. MS-ESI: 231 (M-1). 1

[002558] 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 5.32 (s, 2H).

[002559] Steps 3 to 4 used similar procedures to convert compound 593'' to Intermediate 254 shown in Scheme 124 to provide Intermediate 261 from compound 623''. MS-ESI: 346 (M+1).

Scheme 132: Intermediate 262 N'-(tert-butyldimethylsilyl)-4-fluoro-1-((R)-2-hydroxypropyl)-1H-pyrazol-3-sulfonimidamide Step 1: (R)-N-(tert-butyl )-4-fluoro-1-(2-hydroxypropyl)-1H-pyrazol-3-sulfonamide

[002560] To a stirred solution of N-(tert-butyl)-4-fluoro-1H-pyrazol-5-sulfonamide (1.0 g, 4.52 mmol) in DMF (20 ml) under nitrogen was added K2CO3 (1.87 g, 13.56 mmol) and (R)-2-methyloxirane (524 mg, 9.04 mmol). The resulting solution was stirred for 16 h at 100 °C. The reaction was quenched with 25 ml of water and extracted with 3x30 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 820 mg (65.0%) of the title compound as a yellow solid. MS-ESI: 280 (M+1). Step 2: (R)-4-fluoro-1-(2-hydroxypropyl)-1H-pyrazol-3-sulfonamide

[002561] To stirred concentrated HCl (10 ml) was added (R)-N-

(tert-butyl)-4-fluoro-1-(2-hydroxypropyl)-1H-pyrazol-3-sulfonamide (820 mg, 2.94 mmol) in portions at 0°C. The resulting solution was stirred for 2 h at RT and then concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc (100%). This resulted in 600 mg (91.5%) of the title compound as a yellow oil. MS-ESI: 224 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 4.7 Hz, 1H), 7.68 (s, 2H), 5.03 (d, J = 4.3 Hz, 1H ), 4.09-3.90 (m, 3H), 1.07 (d, J = 5.8 Hz, 3H). Ar-H at 7.98 (d, J = 4.7 Hz, 1H) correlates with CH 2 at 4.09-3.90 (m, 3H) in NOESY.

[002562] Steps 3 through 4 used similar procedures to convert compound 588" to Intermediate 253 shown in Scheme 123 to provide Intermediate 262 from compound 626". MS-ESI: 337 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 4.8 Hz, 1H), 6.86 (s, 2H), 5.00 (sl, 1H), 4.07-3 .89 (m, 3H), 1.10-1.02 (m, 3H), 0.86 (s, 9H), 0.04 (s, 6H). Scheme 133: Intermediate 263 N'-(tert-butyldimethylsilyl)-1-cyclopropyl-1H-pyrazol-3-sulfonimidamide Step 1: 1-cyclopropyl-3-nitro-1H-pyrazole

[002563] To a stirred solution of 3-nitro-1H-pyrazole (20.0 g, 177 mmol) and cyclopropylboronic acid (30.4 g, 353 mmol) in DCE (500 ml), was added 2,2'- bipyridine (27.6 g, 177 mmol) dripped at

RT. To the above solution, Na2CO3 (18.8 g, 177 mmol) and Cu(OAc)2 (32.1 g, 177 mmol) were added portionwise at RT. The resulting mixture was stirred for 16 h at 70 °C under air. The mixture was allowed to cool to RT, then filtered. The filter cake was washed with EtOAc (100 ml). The filtrate and wash were combined and concentrated in vacuo. The residue was diluted with water (500 ml), extracted with EtOAc (3x500 ml). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in the title compound (12.0 g, 44.3%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.5 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 3.96 (tt, J = 7.5, 3.9 Hz, 1H), 1.21-1.13 (m, 2H), 1.13-1.03 (m, 2H). Cyclopropane CH at 3.96 (tt, J = 7.5, 3.9 Hz, 1H) correlates with Ar-H at 8.13 (d, J = 2.5 Hz, 1H) in NOESY. Step 2: 1-cyclopropyl-1H-pyrazol-3-amine

[002564] To a stirred solution of 1-cyclopropyl-3-nitro-1H-pyrazole (12.0 g, 78.4 mmol) in MeOH (50 mL) was added Pd/C (10% by weight, 120 mg ) in portions at RT under nitrogen. The mixture was stirred for 16 h at RT under hydrogen with a hydrogen balloon, then filtered through a Celite filter and concentrated in vacuo. This resulted in the title compound (8.68 g, 90%) as a pale yellow solid. MS-ESI: 124 (M+1). Step 3: 1-Cyclopropyl-1H-pyrazol-3-sulfonyl chloride

[002565] To a stirred solution of 1-cyclopropyl-1H-pyrazol-3-amine (1.0 g, 8.13 mmol) in ACN (10 ml) under nitrogen was added HBF4 (40 wt% in water, 2.68 g, 12.2 mmol) by dripping at 0 °C. To the above solution, tert-butyl nitrite (1.26 g, 12.2 mmol) was added dropwise with stirring at 0 °C. The resulting solution was stirred for 1 h at 0 °C. This solution was designated A. To a stirred solution of CuCl (2.41 g, 24.4 mmol) in ACN (5 mL), SO2 (g) was introduced.

bubbled for 10 min at 0 °C, this solution was designated solution B. To solution B, solution A was added dropwise with stirring at 0 °C for 5 min. The resulting solution was stirred for 10 min at 0 °C, then allowed to react, with stirring, for a further 3 h at RT. The reaction was quenched with water/ice (10ml) and then extracted with DCM (2x30ml). The organic layers were combined and washed with brine (30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in the title compound (1.5 g, crude product) as a yellow oil, which was used in the next step without further purification. Step 4: 1-cyclopropyl-1H-pyrazol-3-sulfonamide

[002566] To a stirred DCM (25 ml), NH3 (g) was bubbled through for 15 min at 0 °C, this was followed by the addition of 1-cyclopropyl-1H-pyrazol-3-sulfonyl chloride (1.50 g , crude product from last step) in DCM (10 ml) by dropping at 0°C. The resulting solution was stirred for 1 h at RT and then concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in the title compound (250 mg, 16.4% over two steps) as a white solid. MS-ESI: 186 (M-1).

[002567] Steps 5 through 6 used similar procedures to convert compound 588'' to Intermediate 253 shown in Scheme 123 to provide Intermediate 263 from compound 631''. MS-ESI: 301 (M+1). Scheme 134: Intermediate 264

2,3-Bis(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002568] Step 1: 3-Iodo-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002569] To a stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (2.0 g, 9.89 mmol) in TFA (20 ml) under nitrogen, NIS (3.34 g, 14.8 mmol) was added in portions at 0 °C. The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated in vacuo. The residue was diluted with 50 ml of water and then extracted with 3x80 ml of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (9:1). This resulted in 2 g (61.6%) of the title compound as a brown solid. MS-ESI: 329 (M+1). Step 2: 2,3-Bis(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

[002570] To a stirred solution of 3-iodo-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (450 mg, 1.37 mmol) in DMF (5 ml) in a sealed tube under nitrogen, (1,10-phenanthroline) (trifluoromethyl)copper(I) (1.72 g, 5.48 mmol) was added. The resulting solution was stirred for 16 h at 45 °C. Solids were removed by filtration. The filtrate was purified by prep HPLC. using the following conditions: Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 um; Mobile Phase A: Water (10 mM NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 20% B to 35% B for 10 min; UV 254 nm; RT: 9.14 min. This resulted in 150 mg (40.4%) of the title compound as a yellow solid.

dark watch. MS-ESI: 271 (M+1). Scheme 135: Intermediate 265 (2,3-Bis(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[002571] To a stirred solution of 2,3-bis(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (125 mg, 0.46 mmol) in THF (15 ml ) under nitrogen, NaH (60% by weight, 56 mg, 1.39 mmol) was added in portions at 0 °C. Thereto, DMAP (28 mg, 0.23 mmol) was added at 0 °C. The resulting solution was stirred for 20 min at 35 °C. To the above solution, 2,2,2-trichloroethyl carbonchloridate (1.96 g, 9.25 mmol) was added dropwise with stirring at 0°C. The resulting solution was stirred for 3 days at 35 °C. The reaction was then quenched with 30 ml of water/ice. The resulting solution was extracted with 3x40 ml of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was eluted from a silica gel column with EtOAc/PE (1:9). This resulted in 13 mg (6.2%) of the title compound as a yellow solid. MS-ESI: 445/447/449 (M+1).

Example 1 (Compound 165) N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide (Scheme 1) Examples 2 and 3 (Compounds 165a and 165b) (R)- and (S)-N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxypropan- 2-yl)thiazol-2-sulfonimidamide Step 1: N-(tert-butyldimethylsilyl)-N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxy -propan-2-yl)thiazol-2-sulfonimidamide

[002572] In a 50 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol-2- sulfonimidamide (206 mg, 0.61 mmol) in THF (10 ml). To the above solution, NaH was added

(60% by weight of oil dispersion, 73.6 mg, 1.84 mmol). The resulting solution was stirred for 10 min at RT. Then, a solution of phenyl (5-fluoro-2,4-diisopropylpyridin-3-yl)carbamate (194 mg, 0.61 mmol) in THF (10 ml) was added to the above solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at RT. The reaction was then stopped with the addition of 10 ml of water. The resulting solution was extracted with 5x20 ml of EtOAc. The organic phases were combined and concentrated. This resulted in 360 mg of the crude title compound as a pale yellow oil. MS-ESI: 558(M+1). Step 2: N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide

[002573] In a 50 ml round bottom flask was placed N-(tert-butyldimethylsilyl)-N'-((5-fluoro-2,4-di-iso-propyl-pyridin-3-yl)carbamoyl) -5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide (360 mg, crude product) in THF (5 ml) and HF pyridine (0.10 ml). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The crude product was purified by prep HPLC. with the following conditions: Column, XBridge BEH130 Prep C18 OBD, 19*150 mm 5 µm; mobile phase, water (10 mM NH4HCO3) and ACN (30% to 60% gradient over 7 min); Detector, 254/210 nm. This resulted in 70 mg of Example 1 as an off-white solid. MS-ESI: 444 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.76 (sl, 3H), 5.82 (s, 1H), 3.25 - 3.05 (m, 2H), 1.53 (s, 6H), 1.18 (d, J = 6.9 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H) . Step 3: Chiral Resolution

[002574] The product (100 mg, Example 1) was separated with the following condition: Column: CHIRALPAK ID, 2*25 cm (5 µm); Mobile Phase A: Hex grade HPLC (0.1% FA), Phase B: EtOH grade HPLC; Flow rate: 20 ml/min; Gradient: 15% B to 15% B in 18 min; 220/254 nm; Rt1: 9.555 min; Rt2: 14.358 min. This resulted in 24.6 mg (97.9%ee,

49.2%) of Example 2 (fast elution) as a white solid and 22.8 mg (98.9%ee, 45.6%) of Example 3 as a white solid. Absolute stereochemistry has not been confirmed. 1

[002575] Example 2: MS-ESI: 444 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.76 (sl, 3H), 5.82 (s, 1H), 3.25 - 3.05 (m, 2H), 1.53 (s, 6H), 1.18 (d, J = 6.9 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H) . 1

[002576] Example 3: MS-ESI: 444 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.76 (sl, 3H), 5.82 (s, 1H), 3.25 - 3.05 (m, 2H), 1.53 (s, 6H), 1.18 (d, J = 6.9 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H) . Table 15. The examples in the following table were prepared using conditions similar to those described in Example 1 and Scheme 1 from appropriate starting materials. Exemplary Number- Exacted Mass with Structure IUPAC Name plo t [M+H]+ post N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-4-(2 - 4,163,444 hydroxypropan-2-yl)thiazol-2-sulfonimidamide N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-5,128yl)carbamoyl )-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide N'-((2,4-diisopropylpyridin-3-yl)carbamoyl)-2-(2-6 110 426 hydroxypropan-2 -yl)thiazol-5-sulfonimidamide

Example 7 (Compound 164) N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (Scheme 1A) Step 1: tert-Butyl (N-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidoyl)carbamate

[002577] In a 50 ml round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed (amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)- tert-butyl λ6-sulfanoylidene)carbamate (327 mg, 1.02 mmol) in THF (10 mL). To the stirred solution, NaH (60% by weight of oil dispersion, 122 mg, 3.05 mmol) was added. The resulting solution was stirred for 10 min at RT. Then, a solution of phenyl N-[5-fluoro-2,4-bis(propan-2-yl)pyridin-3-yl]carbamate (322 mg, 1.02 mmol) in THF (10 mL) has been added. The resulting solution was allowed to react, with stirring, for an additional 2 h at RT. The reaction was then stopped with the addition of 3 ml of water. The resulting mixture was concentrated. This resulted in 500 mg of the crude title compound as a yellow oil. MS-ESI: 544 (M+1). Step 2: N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002578] In a 50 ml round bottom flask was placed (N-((5-fluoro-2,4-diisopropylpyridin-3-yl)-carbamoyl)-2-(2-hydroxypropan-2-yl tert-butyl)thiazole-5-sulfonimidoyl)carbamate (500 mg of crude product) in HCl (4M)/dioxane (20 ml). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The crude product was purified by prep HPLC. with the following conditions: Column, XBridge Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water (10 mM NH4HCO3) and ACN (5% to 41% gradient in 6 min); Detector, 254/210 nm. This resulted in 90 mg of Example 7 as an off-white solid. MS-ESI: 444 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.86 (s, 2H), 6.26 (s, 1H), 3.29-3.05 (m, 2H), 1.49 (s, 6H), 1.20-0.99 (m, 12H). Table 16. The examples in the following table were prepared using conditions similar to those described in Example 7 and Scheme 1A from appropriate starting materials. Exam-Number Exa-Target Mass Structure IUPAC Name by Note [M+H]+ Final N'-((1,2,3,5,6,7-hexa-

The NH2 hydrodicyclopen-

SSON ta[b,e]pyridin-8-8 167 HO N HN N 422 yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide Example 9 (Compound 159) N'-(( 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3 -sulfonimidamide (scheme 2)

Step 1: N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonimidamide

[002579] In a 50 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl- 1H-pyrazol-3-sulfonoimidamide (160 mg, 0.41 mmol) in THF (10 ml). To the stirred solution, NaH (60% by weight of oil dispersion, 48.7 mg, 1.22 mmol) was added at 0 °C. The resulting solution was stirred for 10 min at RT. Then, 2,2,2-trichloroethyl (1,2,2,2-trichloroethyl 1,2,2,2-trichloroethyl (142 mg, 0.41 mmol) (142 mg, 0.41 mmol) was added to the reaction solution. The resulting solution was allowed to react, with stirring, for an additional 2 h while the temperature was maintained at 40 °C in an oil bath. The reaction was then stopped with the addition of 10 ml of H2O. The resulting solution was extracted with 5x20 ml of EtOAc, and the organic layers were combined and concentrated. The residue was purified using TLC with DCM/MeOH = 10:1. This resulted in 230 mg (95.4%) of the title compound as a pale yellow solid. MS-ESI: 595 (M+1). Step 2: N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1 -phenyl-1H-pyrazol-3-sulfonimidamide

[002580] In a 50 ml round bottom flask, N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonimidamide (230 mg, 0.39 mmol) in THF (8 ml). To the above solution, HF-pyridine (0.1 ml) was added dropwise. The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated. The crude product was purified by prep HPLC. with the following conditions: Speaker, XBridge Prep C18 OBD, 19*150 mm 5 um; mobile phase,

water (10 mM NH4HCO3+0.1% NH3.H2O) and ACN (10% to 54% gradient over 6 min); Detector, UV, 210/254 nm.

This resulted in 102 mg (53.8%) of Example 9 as an off-white solid.

MS-ESI: 481 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.58 (s, 2H), 7.52 (s, 5H), 6.75 (s, 1H), 5.43 (s, 1H), 2.79 (t, J = 7.6 Hz, 4H), 2.71 (t, J = 7.5 Hz, 4H), 2.00-1.80 (m, 4H) , 1.34 (s, 6H). Table 17. The examples in the following table were prepared using conditions similar to those described in Example 9 and Scheme 2 from appropriate starting materials.

Number Mass Example with Structure IUPAC Name Exact in rank [M+H]+ N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8 - 10 135 419 yl)carbamoyl)-4-propionylthiophene-2-sulfonimidamide N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-11 119 389 yl)carbamoyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide 1-(difluoromethyl)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopen-12) 122 425 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopene) - ta[b,e]pyridin-8-13 125 442 yl)carbamoyl)-4-((dimethylamino)methyl)benzenesulfonimidamide

Number Mass Example with Structure IUPAC Name Exact in rank [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopent-14 126 [b,e]pyridin-8-yl)carbamoyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide 3-fluoro-5-(2-hydroxypropan-2-yl)-N'-((1', 5',6',7'-tetrahydro-2'H-spiro[cyclopropane-15 101 465 1,3'-dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)thiophene-2 - 4-(2-hydroxypropan-2-yl)-N'-((1',5',6',7'-tetrahydro-2'H-spiro[cyclopropane-16 114 1,3'-) sulfonimidamide 447 dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)thiophene-2-sulfonimidamide N'-((3-ethyl-2-methyl-6,7-dihydro-5H-cyclopenta[b] ]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((3-isopropyl- 2-methyl-6,7-dihydro-5H- 18 116 438 cyclopenta[b]pyridin-4-yl)carbamoyl)thiazol-5-sulfonimidamide

Number Mass Example with Structure IUPAC Name Exact in rank [M+H]+ 4-((dimethylamino)methyl)-N'-((1,2,3,5,6,7-hexa- 19 130 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)benzenesulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b, e]pyridin-8-20 170 494 yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-4-(methoxymethyl)thiazol-5-sulfonimidamide 1-isopropyl-N'-((3-methyl-1 1-isopropyl-N'-((1 ',5',6',7'-tetrahydro-2'H-spiro[cyclopropane-1,3'- 22 172 dicyclopent-415 ta[b,e]pyridin]-8'-yl)carbamoyl)- 1H-pyrazol-3-sulfonimidamide N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-23 173 405 yl)carbamoyl)-4-isopropylthiophen- 2- sulfonimidamide

Number Mass Example with- Structure IUPAC Name Exact in rank [M+H]+ N'-((2-cyclopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4 - 24 174 yl)carbamoyl)-3-fluoro-453 5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide N'-((2-cyclopropyl-3-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide N'-((2-cyclopropyl-6,7-dihydro -5H-cyclopenta[b]pyridin-4- 26 176 yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 4-fluoro-N'-((1,2,3, 5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-27 177 439 yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

N'-((2,3-dihydro-1H-cyclopenta[c]quinolin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Example 28 (Compound 118) N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxyethyl)-2- (2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (Scheme 2A) Step 1: N-(tert-butyldimethylsilyl)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N'-(( 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002581] In a 100 ml round bottom flask was placed N-(tert-butyldimethylsilyl)-4-(2-((tert-butyldimethyl-silyl)oxy)ethyl)-2-(2-hydroxypropan-2- yl)thiazol-5-sulfonimidamide (200 mg, 0.41 mmol) in THF (15 ml). To the above solution, NaH (60% by weight of oil dispersion, 32.8 mg, 0.82 mmol) was added, then (1,2,3,5,6,7-hexahydrodicyclopenta[b,e 2,2,2-Trichloroethyl]pyridin-8-yl)carbamate (142 mg, 0.41 mmol) was added to the reaction solution. The resulting solution was stirred for 30 min at RT. The reaction was then stopped with the addition of 5.0 ml of water. The resulting solution was extracted with 3x15 ml of EtOAc, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 210 mg (75%) of the title compound as a yellow oil. MS-ESI: 694 (M+1). Step 2: N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-

yl)carbamoyl)-4-(2-hydroxyethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002582] In a 100 ml round bottom flask was placed N-(tert-butyldimethylsilyl)-4-(2-((tert-butyldimethyl-silyl)oxy)ethyl)-N'-((1,2, 3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (200 mg, 0.29 mmol) in HCl in dioxane (10 ml, 4M). The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated. The crude product was purified by prep HPLC. with the following conditions: Column, XBridge Prep OBD C18, 30*150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (4% to 28% gradient in 5 min); Detector, UV 254/220 nm. This resulted in 90 mg (67%) of Example 28 as a white solid. MS-ESI: 466 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76 (sl, 2H), 6.19 (s, 1H), 4.90-4.70 (sl, 1H) , 3.80-3.60 (m, 2H), 3.20-3.00 (m, 2H), 2.90-2.60 (m, 8H), 2.10-1.80 (m, 2H), 4H), 1.48 (d, J = 6.0 Hz, 6H). Table 18. The examples in the following table were prepared using conditions similar to those described in Example 28 and Scheme 2A from appropriate starting materials. Number Mass Example with Structure IUPAC Name Exact in rank [M+H]+ N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8 -yl)carbamoyl)-4- 29 150 452 (hydroxymethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Number Mass Example with Structure IUPAC Name Exact in rank [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b] ,e]pyridin-8- 121 yl)carbamoyl)-4-480 (hydroxymethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide N'-((3-hydroxy-1,2, 3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-31,178,438yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide N'-( (4,6-diisopropyl-2-(trifluoromethyl)pyrimidin-5- 32 179yl)carbamoyl)-4-525(hydroxymethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Example 34 (Compound 107)

N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene- 2-sulfonimidamide (scheme 2B)

Step 1: N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide

[002583] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonoimidamide (250mg, 0.72mmol) in THF (10ml). To the above solution, NaH (60% by weight of oil dispersion, 57.2 mg, 1.43 mmol) was added. The resulting solution was stirred for 10 min at RT. Then, 2,2,2-trichloroethyl (1,2,2,2-trichloroethyl (251 mg, 0.72 mmol) (251 mg, 0.72 mmol) was added to the reaction solution. The resulting solution was allowed to react, with stirring, for a further 16 h at 30°C. The reaction was then quenched by the addition of 10 ml of water. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 270 mg (68.6%) of the title compound as a white solid. MS-ESI: 549 (M+1). Step 2: N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5 -methylthiophene-2-sulfonimidamide

[002584] In a 50 ml round bottom flask, N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide (270 mg, 0.49 mmol) in CH3OH (10 mL). To the above solution, silica gel (5.0 g) was added. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (8:1). The crude product was purified by prep HPLC. with the following conditions: Column, Sunfire Prep C18 OBD, 10 um, 19*250 mm; mobile phase, water (0.1% FA) and ACN (10% to 40% gradient over 7 min); Detector, UV.

This resulted in 100 mg (46.78%) of Example 34 as a white solid.

MS-ESI: 435 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ: 8.72 (s, 1H), 8.14 (s, 1H), 7.64 (sl, 2H), 7.48 (s, 1H), 5 .11 (sl, 1H), 2.81-2.74 (m, 4H), 2.73-2.71 (m, 4H), 2.54 (s, 3H), 1.99-1.92 (m, 4H), 1.44 (s, 6H). Table 19. The examples in the following table were prepared using conditions similar to those described in Example 34 and Scheme 2B from appropriate starting materials.

Number Mass Example with Structure IUPAC Name Exact in rank [M+H]+ N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8 - 35 155 yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b, e]pyridin-8-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-sulfonimidamide N'-((1,2,3,5, 6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 3-fluoro-N'-( (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8- 38 105 439 yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide

Number Mass Example with Structure IUPAC Name Exact in rank [M+H]+ 4-(2-hydroxypropan-2-yl)-N'-((3-methyl-1,2,3,5,6 ,7-hexa-39 141 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide 3-fluoro-5-(2-hydroxypropan-2-yl)-N'-(( 3-methyl-1,2,3,5,6,7-hexa-40 103 453 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide N'-((3,3 -dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene- 2-sulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-42 102 467 yl)carbamoyl)-3- fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide N'-((3,5-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e) ]pyridin-8-43 131 449 yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Number Mass Example with Structure IUPAC Name Exact in rank [M+H]+ N'-((3,5-dimethyl-1,2,3,5,6,7-hexahydrodicyclopent- 44 123 [b,e]pyridin-8-yl)carbamoyl)-4-isopropylthiophen-2-sulfonimidamide 1-(difluoromethyl)-N'-((1',5',6',7'-tetrahydro-2 'H-spiro[cyclopropane-1,3'- 45 180 423 dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (4-((dimethylamino)methyl) - tert-Butyl N'-((1,2,3,5,6,7-hexahydrodicyclopen- 46 113 514 ta[b,e]pyridin-8-yl)carbamoyl)phenylsulfonimidoyl)carbamate N'-( (2-cyclopropyl-3-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- 4-(2-hydroxypropan-2-yl)-N'-((2-isopropyl-6,7-dihydro-5H-48 182 423 cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2 sulfonimidamide - sulfonimidamide

Example 49 (Compound 183) N'-((3-fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan -2-yl)thiazol-5-sulfonimidamide (Scheme 3) Step 1: 2-(2-Hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002585] In a 100 ml round bottom flask was placed N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-sulfonoimidamide (2.0 g, 5.96 mmol) in dioxane (50 ml) and aqueous HCl (10 ml, 12 M). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. This resulted in 2.0 g of the crude title compound as a white solid. MS-ESI: 222 (M+1). Step 2: N'-((3-fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxy-propan- 2-yl)thiazol-5-sulfonimidamide

[002586] In a 25 ml round bottom flask, a solution of (3-fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate was placed of 2,2,2-trichloroethyl (66 mg, 0.18 mmol) in THF (2.0 ml). This was followed by the addition of NaH (60% by weight of oil dispersion, 14.4 mg, 0.36 mmol) at 0°C. The resulting solution was stirred for 10 min at RT. Thereto, 2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-sulfonoimidamide (40 mg, 0.18 mmol) was added. The resulting solution was stirred overnight at 45°C. The reaction was then quenched by the addition of 0.5 ml of water. The resulting mixture was concentrated.

The crude product was purified by prep HPLC. with the following conditions: Column, Sunfire Prep C18 OBD, 10 um, 19*250 mm; mobile phase, water (0.05% FA) and ACN (5% to 30% gradient over 7 min); Detector, UV.

This resulted in 5.4 mg (6.8%) of Example 49 as a white solid.

MS-ESI: 440 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.10 (s, 1H), 5.99-5.60 (m, 1H), 3.00-2.60 ( m, 8H), 2.10-1.90 (m, 2H), 1.51 (s, 6H). Table 20. The examples in the following table were prepared using conditions similar to those described in Example 49 and Scheme 3 from appropriate starting materials.

Exemplary Number- Exa- Mass with Structure IUPAC Name plo note [M+H]+ rank N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin -8- 50 154 yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-4-sulfonimidamide Example 51 (Compound 120)

4-((Dimethylamino)methyl)-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-N-methylbenzenesulfonimidamide (scheme 3A)

Step 1: 4-((Dimethylamino)methyl)-N'-methylbenzenesulfonimidamide

[002587] To a 50 ml round bottom flask, N-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-N'-methylbenzenesulfonimidamide (600 mg, 1.76 mmol) in DCM (3. 0 ml) at RT. To this stirred solution, TFA (3 ml, 40 mmol) was added dropwise. The resulting mixture was stirred for 30 min and concentrated under reduced pressure. The crude product (500 mg) was purified by prep HPLC. with the following conditions (Column: XBridge Prep OBD C18, 30x150 mm, 5 um; Mobile Phase A: water (10 mM, NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 5 % B to 45% B in 8 min; 254/210 nm; Rt: 6.13 min) to provide the title compound (250 mg, 62.6%) as a white solid. MS-ESI: 228 (M+1). Step 2: 4-((Dimethylamino)methyl)-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-N-methylbenzenesulfonimidamide

[002588] In a 50 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-((dimethylamino)methyl)-N'-methylbenzenesulfonimidamide (180 mg, 0.79 mmol) in THF was placed (10 ml) at 0°C. To a stirred solution, NaH (60% by weight of oil dispersion, 63.2 mg, 1.58 mmol) was added in portions at 0°C. The resulting mixture was stirred for 15 min at 0°C. To the above mixture, 2,2,2-trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (277 mg, 0. 79 mmol) in THF (3 ml) by dripping at 0°C. The resulting mixture was stirred for an additional 2h at RT. The reaction was quenched by the addition of water/ice (0.5 ml) at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product (300 mg) was purified by prep HPLC. with the following conditions (Column: XBridge Prep OBD C18 30x150 mm 5 µm; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN (5% to 50% gradient for 7 min),

flow rate: 60 ml/min; UV detector 254/210 nm; Rt 6.37 min) to provide Example 51 as a white solid (80 mg, 23%). MS-ESI: 428(M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H ), 3.48 (s, 2H), 2.85-2.73 (m, 4H), 2.73-2.65 (m, 4H), 2.44 (s, 3H), 2.17 ( s, 6H), 2.00-1.80 (m, 4H). Example 52 (Compound 162) 2-(2-hydroxypropan-2-yl)-N'-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8 -yl)carbamoyl)thiazol-5-sulfonimidamide (Scheme 4) Step 1: (2-(2-hydroxypropan-2-yl)-N-((3-methyl-1,2,3,5,6,7- tert-butyl hexahydrodicyclopenta[b,e]-pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidoyl)carbamate

[002589] In a 1 L round bottom flask purged and maintained with an inert atmosphere of nitrogen, a solution of (amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo) tert-butyl -λ6-sulfanoylidene)carbamate (12.8 g, 40 mmol) in THF (300 ml). This was followed by the addition of NaH (60% by weight of oil dispersion, 2.66 g, 66.4 mmol) in several batches at 0°C. The resulting solution was stirred for 20 min at RT. Thereto, a solution of N-(3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide ( 7.5 g, 27 mmol) in DMF (50 ml) by drip with stirring at 0°C. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched by the addition of 10 ml of H2O. The resulting solution was extracted with 2x300 ml of EtO-

B.C. The combined organic layer was washed with 3x200 ml of H 2 O, dried over anhydrous sodium sulfate and concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 3.5 g (24.6%) of the title compound as a white solid. MS-ESI: 536 (M+1). Step 2: 2-(2-hydroxypropan-2-yl)-N'-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamoyl)thiazole-5-sulfonimidamide

[002590] In a 500 ml round bottom flask, a solution of (2-(2-hydroxypropan-2-yl)-N-((3-methyl-1,2,3,5,6,7 tert-butyl-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidoyl)carbamate (3.5g, 6.53mmol) in dioxane (210ml). This was followed by the addition of HCl (52.5 ml, 12 M) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at RT. The pH value of the solution was adjusted to 7 to 8 with Na2CO3 (1.6M). The resulting solution was extracted with 4x500 ml of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep HPLC. with the following conditions: Speaker, XBridge Prep C18 OBD, 19*150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (4% to 22% gradient over 6 min); Detector, 220/254 nm UV. This resulted in 2 g (71%) of Example 52 as a white solid. MS-ESI: 436 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.08 (s, 1H), 7.89 (sl, 2H), 6.28 (s, 1H), 3.03 -2.98 (m, 1H), 2.83-2.79 (t, J = 7.2 Hz, 2H), 2.72-2.61 (m, 4H), 2.27-2.20 (m, 1H), 2.07-1.92 (m, 2H), 1.51-1.45 (m, 7H), 1.21-1.19 (d, J = 8.0 Hz, 3H ). Example 53 (Compound 104)

4-(2-hydroxypropan-2-yl)-5-methyl-N'-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl )carbamoyl)thiazol-2-sulfonimidamide (Scheme 4A) Step 1: N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methyl-N'-((3-methyl-1, 2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-2-sulfonimidamide

[002591] In a 100 ml round bottom flask was placed N-(3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)-1H -imidazole-1-carboxamide (150 mg, 0.43 mmol) in DMF (15 ml). To the stirred solution, NaH (60% by weight of oil dispersion, 56.1 mg, 1.29 mmol) was added. This was followed by the addition of a solution of N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiazol-2-sulfonimidamide (120 mg, 0.43 mmol) in DMF (5. 0 ml). The resulting solution was stirred for 16 h at 30 °C in an oil bath. The reaction was then stopped with the addition of 15 ml of water. The resulting solution was extracted with 2x30 ml of EtOAc. The combined extracts were dried with anhydrous sodium sulfate and concentrated. This resulted in 180 mg (74.4%) of the title compound as a yellow solid. MS-ESI: 564 (M+1). Step 2: 4-(2-hydroxypropan-2-yl)-5-methyl-N'-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiazol-2-sulfonimidamide

[002592] In a 50 ml round bottom flask was placed N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methyl-N'-((3-methyl-1, 2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-2-sulfonimidamide (180 mg, 0.32 mmol) in THF (15 ml) was added to the stirred solution. - TBAF (250 mg, 0.96 mmol) was added. The resulting solution was stirred for 5 h at RT. The resulting mixture was concentrated. The residue

duo was eluted from silica gel with DCM/MeOH (10:1). The crude product was purified by prep HPLC. with the following conditions: Column, SunFire Prep C18 OBD, 19*150mm 5um; mobile phase, water (0.1% FA) and ACN (12% to 22% gradient over 10 min); Detector, UV 254 nm.

This resulted in 40 mg (27.87%) of Example 53 as a white solid.

MS-ESI: 450 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 5.96 (s, 1H), 2.91-3.04 (m, 1H), 2.85-2.80 ( m, 2H), 2.75-2.62 (m, 4H), 2.44 (s, 3H), 2.25-2.15 (m, 1H), 2.00-1.90 (m, 1H), 2H), 1.58(s, 6H), 1.42-1.40 (m, 1H), 1.20(d, J = 7.8Hz, 3H) Table 21. The examples in the following table were prepared using conditions similar to those described in Example 53 and Scheme 4A from appropriate starting materials.

Example- Number Exa-Structure IUPAC Name plo in Final Target ta [M+H]+ 4-(hydroxymethyl)-2-(2-hydroxypropan-2-yl)-N'-((3-methyl-1,2) ,3,5,6,7-hexa-54,168,466 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide Example 55 (Compound 158)

N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-methyl- 1H-pyrazol-3-sulfonimidamide (scheme 5)

[002593] In a 50 ml round bottom flask purged and maintained with an inert atmosphere of nitrogen, N-(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin -8-yl)-1H-imidazole-1-carboxamide (246 mg, 0.92 mmol) in DMF (5 ml). To the above solution, 5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-sulfonimidamide (200 mg, 0.92 mmol) and NaH (60 wt. oil, 73.6 mg, 1.84 mmol). The resulting solution was stirred for 1 h at RT.

The resulting mixture was quenched with 3 ml of H2O and concentrated.

The crude product was purified by prep HPLC. with the following conditions: Column, XBridge Prep C18 OBD, 19*150 mm, 5 µm; mobile phase, water (10 mM NH4HCO3+0.1% NH3.H2O) and ACN (5% to 38% gradient in 6 min); Detector, UV 210/254 nm.

This resulted in 8.2 mg (2.14%) of Example 55 as a white solid.

MS-ESI: 419 (M+1). 1H NMR (400 MHz, DMSO-d6) 8.70 (s, 1H), 7.47 (s, 2H), 6.49 (s, 1H), 5.51 (s, 1H), 4.04 ( s, 3H), 2.90-2.60 (m, 8H), 2.00-1.80 (m, 4H), 1.48 (s, 6H). Table 22. The examples in the following table were prepared using conditions similar to those described in Example 55 and Scheme 5 from appropriate starting materials.

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-56 157 yl)carbamoyl)-6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-sulfonimidamide

Example Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-57 156 yl)carbamoyl)-6-(2-hydroxypropan-2-yl)pyridin-3-sulfonimidamide N'-((3,5-diisopropylpyridin-4-yl)carbamoyl)-2-(2- 58 160 426 hydroxypropan-2-yl)thiazol-5-sulfonimidamide 1-isopropyl-N'-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopent-59 129 ta[b,e]pyridin -8-403yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-60 161 9-yl )carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[ b,e]pyridin-8-61 153 450 yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ 2-(2-hydroxypropan-2-yl)-N'-((2-methyl-1,2,3,5,6,7 -hexa-62 152 hydrodicyclopent-436 ta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((1-methyl-1, 2,3,5,6,7-hexa- 63 151 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide N'-((2,2-dimethyl-1,2 ,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-64,147,450yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide 4-oxide of 8-(3-(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-65 146 438 sulphanylidene)ureido)-1,2,3,5,6, 7-hexahydrodicyclopenta[b,e]pyridine 2-(2-hydroxypropan-2-yl)-N'-((2,3,5,6-tetramethylpyridin-4-398yl)carbamoyl)thiazole -5-sulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((2-propyl-6,7-di-N HN N hydro-5H- 67 112 N 424

S S O cyclopenta[b]pyridin-4-

OH O H2N yl)carbamoyl)thiazol-5-sulfonimidamide

Example 68 (Compound 115) N'-((2-fluoro-3,5-diisopropylpyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (Scheme 6) Step 1 : N-(tert-butyldimethylsilyl)-N'-((2-fluoro-3,5-diisopropylpyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002594] In a 100 ml round bottom flask, 2-fluoro-4-isocyanato-3,5-diisopropylpyridine (240 mg, 1.22 mmol) in THF (10 ml) was placed into the stirred solution, NaH (60 wt% oil dispersion, 59 mg, 2.45 mmol) and N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (410 mg) were added. , 1.22 mmol). The resulting solution was stirred for 2 h at 25 °C. The reaction was then quenched by the addition of 20 ml of water. The resulting solution was extracted with 2x20 ml of EtOAc, and the organic layers combined and dried and concentrated. This resulted in 400 mg (59%) of the title compound as a yellow solid. MS-ESI: 558 (M+1). Step 2: N'-((2-fluoro-3,5-diisopropylpyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002595] In a 100 ml round bottom flask was placed N-(tert-butyldimethylsilyl)-N'-((2-fluoro-3,5-diisopropyl-pyridin-4-yl)carbamoyl)-2 -(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (400 mg, 0.72 mmol) in THF (10 ml) and HF-pyridine (31 mg, 1.08 mmol, 70% by weight). The resulting solution was stirred for 2 h at 25°C. The resulting mixture was concentrated. The crude product was purified by prep HPLC. with the following conditions: Column, XBridge Prep OBD C18, 30*150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (5% to 35% gradient over 6 min); Detector, UV 220/254 nm. This resulted in 200 mg (63%) of Example 68 as a white solid. MS-ESI: 443 (M+1). 1H NMR (400 MHz, CD3OD-d4) δ 8.14 (s, 1H), 7.92 (s, 1H), 3.30-3.00 (m, 2H), 1.59 (s, 6H) , 1.50-1.10 (m, 12H). Example 69 (Compound 106) 3-Fluoro-N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (scheme 7)

[002596] In a 50 ml round bottom flask, 5-fluoro-3-isocyanate-2,4-diisopropylpyridine (120 mg, 0.50 mmol) in THF (15 ml) was placed. To the stirred solution was added NaH (60% by weight of oil dispersion, 60.4 mg, 1.51 mmol). The resulting solution was stirred for 10 min at RT. Then, 3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (150 mg, crude) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h at RT. The reaction was then stopped with the addition of 20 ml of water. The resulting solution was extracted with 5x30 ml of EtOAc, and the combined extract was concentrated. The crude product was purified by prep HPLC. with the following conditions: Column, XBridge Prep C18 OBD, 5 um.19*150 mm;

mobile phase, water (10 mM NH4HCO3) and ACN (5% to 50% gradient over 6 min); Detector, UV (254/210 nm). This resulted in 75 mg (32%) of Example 69 as an off-white solid.

MS-ESI: 461 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.29 (s, 1H), 7.68 (sl, 2H), 6.96 (s, 1H), 5.83 (s, 1H), 3.38-3.17 (m, 2H), 1.45 (s, 6H), 1.22 (d, J = 7.1 Hz, 6H), 1.10 (d, J = 6.7 Hz, 6H). Table 23. The examples in the following table were prepared using conditions similar to those described in Example 69 and Scheme 7 from appropriate starting materials.

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-4-(2-70 148 443 hydroxypropan-2-yl)thiophene-2-sulfonimidamide 4-((dimethylamino)methyl)-N'-((5-fluoro-2,4-di-isopropylpyridin-3-yl)carbamoyl)benzene sulfonimidamide 5- (2-hydroxypropan-2-yl)-N'-((3-methyl-1,2,3,5,6,7-hexa-hydrodicyclopenta[b,e]pyridin-8-yl) carbamoyl)thiazol-2-sulfonimidamide 4-((dimethylamino)methyl)-2-fluoro-N'-((3-methyl-1,2,3,5,6,7-hexa- 73 139 446 hydrodicyclopenta[ b,e]pyridin-8-yl)carbamoyl)benzenesulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ 4-((dimethylamino)methyl)-N'-((3-methyl-1,2,3,5,6,7-hexa- 74 134 428 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)benzenesulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((3-isopropyl-2-phenyl-6,7- dihydro-5H- 75 145 500 cyclopenta[b]pyridin-4-yl)carbamoyl)thiazol-5-sulfonimidamide N'-((3-ethyl-2-phenyl-6,7-dihydro-5H-O NH2

S cyclopenta[b]pyridin-4-

N H

N 76 144 S N yl)carbamoyl)-2-(2-486

N O hydroxypropan-2-

OH yl)thiazol-5-sulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((3-methyl-2-phenyl-6,7-dihydro-5H- cyclopenta[b] pyridin-4-yl)carbamoyl)thiazol-5-sulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((2-phenyl-6,7-dihydro-5H- 78 142 458 cyclopenta[b] ]pyridin-4-yl)carbamoyl)thiazol-5-sulfonimidamide N'-((2,3-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4- 79 138 yl)carbamoyl)- 2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((2-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4- 80 137 yl)carbamoyl )-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((1',5',6',7'-tetra- hydro-2'H-spiro[cyclopropane-81 136 448 1,3'-dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)thiazol-5-sulfonimidamide N'-((2-cyclopropyl- 3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002597] Table 24. The examples in the following table were obtained from chiral HPLC resolutions of racemic examples. The chiral column and eluents are listed in the table. As a convention, the fastest-eluting enantiomer is always listed first in the table, followed by the slower-eluting enantiomer of the pair. The symbol * in a chiral center denotes that the chiral center has been separated, and the absolute stereochemistry at that chiral center has not been determined. For mixtures contained in two chiral centers and if two columns are used to separate the four diastereoisomers, the individual isomers will be listed in the order of fastest column 1/fastest column 2; column 1 fastest/column 2 slower; slowest column 1/fastest column 2; followed by the slowest column 1/slowest column 2.

Number Exemple- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ rank (R) or (S)-N'- ((1,2,3,5,6,7-hexa- hydrodicyclopen-CHIRAL-EtOH ta[b,e]pyridin-8-PAK IG, in Hex 83 128a 422 yl)carbamoyl)-2-(2-2*25 cm (0.1% hydroxypropan-2-(5 µm) ) FA)yl)thiazol-5-sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexahydrodicyclopen-CHIRAL-EtOH ta[b,e]pyridin- 8-PAK IG, in Hex 84 128b 422 yl)carbamoyl)-2-(2-2*25 cm (0.1% hydroxypropan-2-(5 µm)FA)yl)thiazol-5-sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexahydrodicyclopen-CHIRAL EtOH ta[b,e]pyridin-8-ART Celu- in Hex 85 150a yl)carbamoyl)- 4-Lose-SB, 452 (0.1% of (hydroxymethyl)-2-(2-2*25 cm, FA)hydroxypropan-2-5umyl)thiazol-5-sulfonimidamide (R) or (S)- N'-((1,2,3,5,6,7-hexahydrodicyclopen-CHIRAL EtOH ta[b,e]pyridin-8-ART Cellu- in Hex 86 150b yl)carbamoyl)-4-lose-SB , 452 (0.1% (hydroxymethyl)-2-(2-2*25 cm, FA)hydroxypropan-2-5umyl)thiazol-5-sulfonimidamide (R) or (S)-N'-(( 5-fluoro-2,4-di-CHIRAL-EtOH isopropylpyridin-3-PAK ID, in Hex 87 163a yl)carbamoyl)-4-(2-444 2*25 cm (0.1% hydroxypropan-2-(5 µm)FA)yl)thiazol-2-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ post (S) or (R)-N'-((5-fluoro-2,4-di-CHIRAL-EtOH isopropylpyridin -3- PAK ID, in Hex 88 163b yl)carbamoyl)-4-(2-444 2*25 cm (0.1% hydroxypropan-2-(5 µm)FA)yl)thiazol-2-sulfonimidamide (S ) or (R)-N'-((1,2,3,5,6,7-hexahydrodicyclopen-Chiralpak 30% ta[b,e]pyridin-8-91 167a AD, 2*25 MeOH 422 yl)carbamoyl)-5-(2-cm (5 µm) in CO 2 hydroxypropan-2-yl)thiazol-2-sulfonimidamide (R) or (S)-N'-((1,2,3,5,6 ,7-hexahydrodicyclopen-Chiralpak 30% ta[b,e]pyridin-8-92 167b AD, 2*25 MeOH 422 yl)carbamoyl)-5-(2-cm (5 µm) in CO 2 hydroxypropan-2 -yl)thiazol-2-sulfonimidamide (S) or (R)-N'-((5-fluoro-2,4-di-CHIRAL-EtOH isopropylpyridin-3-PAK ID, in Hex 93 164b yl)carbamoyl)- 2-(2-444 2*25 cm (0.1% hydroxypropan-2-(5 µm)FA)yl)thiazol-5-sulfonimidamide (R) or (S)-N'-((5-fluoro- 2,4-di-CHIRAL-EtOH isopropylpyridin-3-PAK ID, in Hex 94 164a yl)carbamoyl)-2-(2-444 2*25 cm (0.1% hydroxypropan-2- (5 um) FA)yl)thiazol-5-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ rank (S) or (R)-N'- ((2,3,5,6,7,8-hexa-

CHIRAL hydro-1H-ART Cellulo-EtOH cyclopentose-SB in Hex 95 161a ta[b]quinolin-9-436 S-5um, (0.1% yl)carbamoyl)-2-(2-250*20 FA) hydroxypropan-2-mmyl)thiazol-5-sulfonimidamide (R) or (S)-N'-((2,3,5,6,7,8-hexa-

CHIRAL hydro-1H-ART Cellulo-EtOH cyclopentoselose-SB in Hex 96 161b ta[b]quinolin-9-436 S-5um, (0.1% yl)carbamoyl)-2-(2-250*20 FA) hydroxypropan-2-mmyl)thiazol-5-sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexahydrodicyclopen-CHIRAL-EtOH ta[b, e]pyridin-8-PAK IC, in Hex 97 159a 481 yl)carbamoyl)-5-(2-2*25 cm, (0.1% hydroxypropan-2-yl)-5um FA) 1-phenyl- 1H-pyrazol-3-sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexahydrodicyclopent-CHIRAL-EtOH ta[b,e]pyridin-8-PAK IC, in Hex 98 159b 481 yl)carbamoyl)-5-(2-2*25 cm, (0.1% hydroxypropan-2-yl)-5um FA) 1-phenyl-1H-pyrazol-3-sulfonimidamide

Number Exemple- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ rank (R) or (S)-N'- ((1,2,3,5,6,7-hexa- EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IC, 99 158a (NH3.Me 419 yl)carbamoyl)-5-(2-2*25 cm, OH 8 hydroxypropan-2-yl) - 5 mM)# 1-methyl-1H-pyrazol-3-sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IC, 100 158b (NH 3 .Me 419 yl)carbamoyl)-5-(2-2*25 cm, OH 8 hydroxypropan-2-yl)-5 mM) 1 -methyl-1H-pyrazol-3-sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Celu- in Hex ta[b, e]pyridin-8-101 157allose-SB (NH 3 .Me 430 yl)carbamoyl)-6-(2-S-5um, OH 8 hydroxypropan-2-yl)- 2*25 cmM) 2-methylpyridine-3 - sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Celu- in Hex ta[b,e]pyridin-8-102 157b Lose-SB (NH3.Me 430 yl)carbamoyl)-6-(2-S-5um, OH 8 hydroxypropan-2-yl)-2*25 cmM) 2-methylpyridine-3-sulfonimidamide (R) or (S )-N'-((3, 5- Diisopropylpyridin-4-Chiralpak EtOH in Hexyl)carbamoyl)-2-(2- 103 160a ID, 2*25 (NH 3 .Me 426 hydroxypropan-2-cm, 5 um OH 8 yl)thiazol-5- mM) sulfonimidamide

Exemplary Compound LC-MS Number Structure IUPAC Name Column Eluents in the [M+H]+ post (S) or (R)-N'-((3,5- EtOH di-isopropylpyridin-4- Chiralpak in Hex (S,R) or (S, S)-2-(2-hydroxypropan-2- These two isomethyl)-N'-((3-methyl-ros elute 1,2,3,5,6,7-hexa- faster at 105 162ab 436 hydrodicyclopen-CHIRAL ART Celluta[b,e]pyridin-8-lose-SB, 2*25 cm, 5 yl)carbamoyl)thiazol-one, EtOH in Hex 5-sulfonimidamide (8 mM NH 3 .MeOH); (S,S) or (S,R)-2- separated into iso-(2-hydroxypropan-2-yl only)-N'-((3-methyl-CHIRALPAK IG, 1,2,3,5) ,6,7-hexa- 20*250 mm, 5 um 106 162aa 436 hydrodicyclopen-EtOH in MTBE ta[b,e]pyridin-8-(NH 3 -MeOH 10yl)carbamoyl)thiazol-mM) 5-sulfonimidamide (R , R) -2-(2-hydroxypropan-2-yl)- These two isomers-N'-((3-methyl-ros elute 1,2,3,5,6,7-hexa- slower in 107 162bb 436 hydrodicyclopen-CHIRAL ART Celluta[b,e]pyridin-8-lose-SB, 2*25 cm, 5 yl)carbamoyl)thiazol-one, EtOH in Hex 5-sulfonimidamide (8 mM NH 3 .MeOH) ; (R,S)-2-(2-separated into iso-hydroxypropan-2-yl)-singlemer in N'-((3-methyl-CHIRALPAK IG, 1,2,3,5,6,7-hexa - 20*250 mm, 5 um 108 162ba 436 hydrodicyclopen-EtOH in MTBE ta[b,e]pyridin-8-(NH 3 -MeOH 10yl)carbamoyl)thiazol-mM) 5-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ rank (S) or (R)-N'- ((1,2,3,5,6,7-hexa- EtOH

CHIRAL hydrodicyclopen- on ART Celluta[b,e]pyridin-8-MTBE 109 156allose-SB S, 416 yl)carbamoyl)-6-(2-(NH 3 - 2*25 cm, hydroxypropan-2-MeOH 5 a 3-10 mM yl)pyridine-3-sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa-EtOH

CHIRAL hydrodicyclopen- on ART Celluta[b,e]pyridin-8-MTBE 110 156blose-SB S, 416 yl)carbamoyl)-6-(2-(NH 3 - 2*25 cm, hydroxypropan-2-MeOH 5 a 3-10 mM yl)pyridine-3-sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e) ]pyridin-8-PAK IG, 111 155a (NH3.Me 421 yl)carbamoyl)-4-(2-2*25 cm OH 8 hydroxypropan-2-(5 µm) mM) yl)thiophene-2-sulfonimidamide (S ) or (R)-N'-((1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IG, 112 155b (8,421 yl)carbamoyl)-4-(2-2*25cm NH3.Me hydroxypropan-2-(5 µm)OH)yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((1,2 ,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IG, 113 149a (NH 3 .Me 421 yl)carbamoyl)-5-(2-2* 25 cm OH 8 hydroxypropan-2-(5 µm) mM) yl)thiophene-2-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ rank (S) or (R)-N'- ((1,2,3,5,6,7-hexa- EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IG, 114 149b (NH 3 .Me 421 yl)carbamoyl)-5-(2-2*25 cm OH 8 hydroxypropan-2-(5 µm ) mM) yl)thiophene-2-sulfonimidamide (R) or (S)-3-fluoro-N'-((5-fluoro-2,4-di-EtOH CHIRAL-isopropylpyridin-3- in Hex PAK ID, 115 106a yl)carbamoyl)-5-(2-(NH 3 .Me 461 2*25 cm hydroxypropan-2-OH 8 (5 µm) yl)thiophene-2-mM) sulfonimidamide (S) or (R)-3-fluoro - N'-((5-fluoro-2,4-di-EtOH CHIRAL-isopropylpyridin-3- in Hex PAK ID, 116 106b yl)carbamoyl)-5-(2-(NH3.Me 461 2*25 cm hydroxypropan -2-OH 8(5 µm)yl)thiophene-2-mM)sulfonimidamide (R) or (S)-N'-((5-fluoro-2,4-di-CHIRAL-EtOH isopropylpyridin-3-PAK IF , in Hex 117 148a yl)carbamoyl)-4-(2-443 2*25 cm, (0.1% hydroxypropan-2-5um FA)yl)thiophene-2-sulfonimidamide (S) or (R)- N'-((5-fluoro-2,4-di-CHIRAL-EtOH isopropylpyridin-3-PAK IF, in Hex 118 148b yl)carbamoyl)-4-(2- 443 2*25 cm, (0.1% hydroxypropan-2-5um FA)yl)thiophene-2-sulfonimidamide

Example Number- LC-MS of the compound Structure Name IUPAC Column Eluents by the [M+H]+ post (S) or (R)-N'-((2,2-dimethyl-1,2,3,5, 6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Cellu- on Hex 119 147a ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 450 yl)carbamoyl)-2-(2-2*25 cm , OH 8 hydroxypropan-2-5 mM)yl)thiazol-5-sulfonimidamide (R) or (S)-N'-((2,2-dimethyl-1,2,3,5,6,7-hexa - CHIRAL EtOH hydrodicyclopen-ART Cellu- on Hex 120 147b ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 450 yl)carbamoyl)-2-(2-2*25 cm, OH 8 hydroxypropan- 2-5 mM)yl)thiazol-5-sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b ,e]pyridin-8-PAK IC, 121 107a (NH 3 .Me 435 yl)carbamoyl)-4-(2-2*25 cm, OH 8 hydroxypropan-2-yl)-5 mM) 5-methylthiophene-2 - sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IC, 122 107b (NH 3 .Me 435 yl)carbamoyl)-4-(2-2*25 cm, OH 8 hydroxypropan-2-yl)- 5 mM) 5-methylthiophene-2-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ post (R) or (S)-2-(2-hydroxypropan-2-yl)-N'-((3- isopropyl-2-CHIRAL-EtOH phenyl-6,7-dihydro-PAK IC, in Hex 123 145a 5H- 500 2*25 cm, (0.1% cyclopenta[b]pyridin-5um FA) 4- yl)carbamoyl)thiazol-5-sulfonimidamide (S) or (R)-2-(2-hydroxypropan-2-yl)-N'-((3-isopropyl-2-CHIRAL-EtOH phenyl-6,7-di -hydro-PAK IC, in Hex 124 145b 5H- 500 2*25 cm, (0.1% cyclopenta[b]pyridin-5um FA) 4-yl)carbamoyl)thiazol-5-sulfonimidamide (R) or ( S)-3-fluoro-N'-((1,2,3,5,6,7-hexa-EtOH CHIRAL-hydrodicyclopen- in Hex PAK IG, 125 105a ta[b,e]pyridin-8-(NH 3 .Me 439 20*250 yl)carbamoyl)-5-(2-OH 8mm, 5um hydroxypropan-2-mM)yl)thiophene-2-sulfonimidamide (S) or (R)-3-fluoro-N'- ((1,2,3,5,6,7-hexa-EtOH CHIRAL-hydrodicyclopen- in Hex PAK IG, 126 105b ta[b,e]pyridin-8-(NH3.Me 439 20*250 yl)carbamoyl) -5-(2-OH 8mm, 5um hydroxypropan-2-mM)yl)thiophene-2-sulfonimidamide

Example Number- LC-MS of the compound Structure Name IUPAC Column Eluents by the [M+H]+ post (S) or (R)-N'-((3,3-dimethyl-1,2,3,5, 6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Cellu- on Hex 127 153a ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 450 yl)carbamoyl)-2-(2-2*25 cm , OH 8 hydroxypropan-2-5 mM)yl)thiazol-5-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa - CHIRAL EtOH hydrodicyclopen-ART Cellu- on Hex 128 153b ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 450 yl)carbamoyl)-2-(2-2*25 cm, OH 8 hydroxypropan- 2-5 mM) yl)thiazol-5-sulfonimidamide (R) or (S)-2-(2-CHIRAL hydroxypropan-2-yl)-ART Cellu-EtOH N'-((2,3,5,6 -lose-SB in Hex 129 133a 398 tetramethylpyridin-4-S-5 µm, (0.1% yl)carbamoyl)thiazol-2*25 cm, FA) 5-sulfonimidamide 5 µm (S) or (R)- 2-(2-CHIRAL hydroxypropan-2-yl)-ART Cellu-EtOH N'-((2,3,5,6-Lose-SB in Hex 130 133b 398 tetramethylpyridin-4-S-5 um, (0. 1% yl)carbamoyl)thiazol-2*25cm, FA) 5-sulfonimidamide 5um (R) or (S)-N'-((2-ethyl-6,7-dihydro-5H-IPA in CHIRAL - cycle openta[b]pyridin-Hex:DM PAK IG, 131 137a 4-yl)carbamoyl)-2-(2-=5:1 410 20*250 hydroxypropan-2-(0.1% mm, 5 umyl) thiazol-5-FA) sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ post (S) or (R)-N'-((2-ethyl-6,7-dihydro-5H- IPA in CHIRAL-cyclopenta[b]pyridin-Hex:DC PAK IG, 132 137b 4-yl)carbamoyl)-2-(2-M=5:1 410 20*250 hydroxypropan-2-(0.1% mm , 5 a yl)thiazol-5-FA)sulfonimidamide (S) or (R)-2-(2-hydroxypropan-2-yl)-N'-((1',5',6',7'-tetra - CHIRAL EtOH hydro-2'H-ART Cellulose Hex 133 136a spiro[cycloprolose-SB, (NH3.Me 448 pano-1,3'-dicyclo- 2*25 cm, OH 8 penta[b,e) ]pyridin]-8'-5 mM) yl)carbamoyl)thiazol-5-sulfonimidamide (R) or (S)-2-(2-hydroxypropan-2-yl)-N'-((1',5' ,6',7'-tetra-CHIRAL EtOH hydro-2'H-ART Cellu- on Hex 134 136b spiro[cycloprolose-SB, (NH3.Me 448 pano-1,3'-dicyclo- 2*25 cm , OH 8 penta[b,e]pyridin]-8'-5 mM) yl)carbamoyl)thiazol-5-sulfonimidamide (R, R/S) or (S, R/S)-5-(2-hydroxypropan -2-yl)-CHIRAL-EtOH N'-((3-methyl-PAK IC, in Hex 135 140a 1,2,3,5,6,7-hexa- 436 2*25 cm, (0.1% of hydrodicyclopen-5 a FA) ta[b,e]pyridin-8-yl)carbamoyl)thiazo l-2-sulfonimidamide

Exemplary LC-MS Number of Compound Structure IUPAC Name Column Eluents by the [M+H]+ post (S, R/S) or (R, R/S)-5-(2-hydroxypropan-2-yl) - CHIRAL-EtOH N'-((3-methyl-PAK IC, in Hex 136 140b 1,2,3,5,6,7-hexa- 436 2*25 cm, (0.1% hydrodicyclopen-5um FA) ta[b,e]pyridin-8-yl)carbamoyl)thiazol-2-sulfonimidamide (R,R) or (R,S)-5-(2-hydroxypropan-2-40% Chiralpakyl)-N '-((3-methyl-MeOH AD-H, 1,2,3,5,6,7-hexa-(NH3.Me 137 140aa 2*25 cm 436 hydrodicyclopen-OH 8 (5 µm); b,e]pyridin-8-mM) in Ex. )-N'-((3-methyl-MeOH AD-H, 1,2,3,5,6,7-hexa-(NH3.Me 138 140ab 2*25 cm 436 hydrodicyclopen-OH 8 (5 µm); of ta[b,e]pyridin-8-mM) in Ex. 135 yl)carbamoyl)thiazol-CO 2 2-sulfonimidamide (S,S) or (S,R)-5-(2-hydroxypropan-2-40% of Chiralpakyl)-N'-((3-methyl-MeOH AD-H, 1,2,3,5,6,7-hexa-(NH3.Me 139 140ba 2*25 cm 436 hydrodicyclopen-OH 8 (5 a); from ta[b,e]pyridin-8-mM) in Ex. 136 yl)carba moyl)thiazol-CO2 2-sulfonimidamide (S,R) or (S,S)-5-(2-hydroxypropan-2-40% Chiralpakyl)-N'-((3-methyl-MeOH AD-H, 1,2,3,5,6,7-hexa-(NH3.Me 140 140bb 2*25 cm 436 hydrodicyclopen-OH 8 (5 µm); of ta[b,e]pyridin-8-mM) in Ex. 136 yl)carbamoyl)thiazol-CO 2 2-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents in the [M+H]+ post (R, R) or (R, S)-1-isopropyl-N'-((3-EtOH methyl-1) ,2,3,5,6,7- CHIRAL- in O NH2 O hexa- S PAK IG, MTBE 141 129aa NNN hydrodicyclopen- 403

NNH 2*25 cm (NH 3 -ta[b,e]pyridin-8-(5 µm) MeOH yl)carbamoyl)-1H- 10 mM) pyrazol-3-sulfonimidamide (S,S) or (S,R)- 1-isopropyl-N'-((3-EtOH methyl-1,2,3,5,6,7-CHIRAL- in hexa-PAK IG, MTBE 142 129ab hydrodicyclopen- 403 2*25 cm (NH 3 -ta[b ,e]pyridin-8-(5 µm) MeOH yl)carbamoyl)-1H-10 mM) pyrazol-3-sulfonimidamide (R,S) or (R,R)-1-isopropyl-N'-((3- EtOH methyl-1,2,3,5,6,7-CHIRAL- in O NH 2 O hexa- S PAK IG, MTBE 143 129ba NNN hydrodicyclopen- 403

NNH 2*25 cm (10 mM ta[b,e]pyridin-8-(5 µm) NH 3 -yl)carbamoyl)-1H-MEOH) pyrazol-3-sulfonimidamide (S, R) or (S, S)- 1-isopropyl-N'-((3-EtOH methyl-1,2,3,5,6,7-CHIRAL- in O NH 2 O hexa- S PAK IG, MTBE 144 129bb NNN hydrodicyclopen- 403

N N H 2*25 cm (10 mM ta[b,e]pyridin-8-(5 µm) NH 3 -yl)carbamoyl)-1H-MEOH) pyrazol-3-sulfonimidamide

Example Number- LC-MS of the compound Structure Name IUPAC Column Eluents by the [M+H]+ post (S) or (R)-N'-((3,3-dimethyl-1,2,3,5, 6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Cellu- on Hex 145 127a ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 449 yl)carbamoyl)-4-(2-2*25 cm , OH 8 hydroxypropan-2-5 mM)yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa - CHIRAL EtOH hydrodicyclopen-ART Cellu- on Hex 146 127b ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 449 yl)carbamoyl)-4-(2-2*25 cm, OH 8 hydroxypropan- 2-5 mM)yl)thiophene-2-sulfonimidamide (S) or (R)-4-((dimethylami-CHIRAL EtOH no)methyl)-N'-ART Celu- in Hex ((1,2,3, (R ) or (S)-4-((dimethylamino-CHIRAL EtOH no)methyl)-N'-ART Cellu- in Hex ((1,2,3,5,6,7-hexa-148 130blose-SB, ( NH3.Me 414 hydrodicyclopen- 2*25 cm, OH 8 ta[b,e]pyridin-8-5 mM) yl)carbamoyl)benzenesulfonimidamide

Example Number- LC-MS of the compound Structure Name IUPAC Column Eluents by the [M+H]+ post (R) or (S)-N'-((3,3-dimethyl-1,2,3,5, 6,7-hexa-EtOH CHIRAL- hydrodicyclopen- on Hex PAK IG, 149 126a ta[b,e]pyridin-8-(NH 3 .Me 417 20*250 yl)carbamoyl)-1-OH 8 mm, 5 µm isopropyl -1H-mM) pyrazol-3-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-EtOH CHIRAL-hydrodicyclopen-em Hex PAK IG, 150 126b ta[b,e]pyridin-8-(NH 3 .Me 417 20*250 yl)carbamoyl)-1-OH 8 mm, 5 um isopropyl-1H-mM) pyrazol-3-sulfonimidamide (S, R/S) or (R, R/S)-4-(hydroxymethyl)-2-(2-CHIRAL EtOH hydroxypropan-2-yl)-ART Cellu- in Hex N'-((3-methyl-151 168alose) -SB, (NH 3 .Me 466 1,2,3,5,6,7-hexa- 2*25 cm, OH 8 hydrodicyclopen- 5 mM) ta[b,e]pyridin-8-yl)carbamoyl)thiazole - 5-sulfonimidamide (R, R/S) or (S, R/S)-4-(hydroxymethyl)-2-(2-CHIRAL EtOH hydroxypropan-2-yl)-ART Celu- in Hex N'-(( 3-methyl-152 168blose-SB, (NH 3 .Me 466 1,2,3,5,6,7-hexa- 2*25 cm, OH 8 hydrodicyclopent-5 mM) ta[b,e]pyridin- 8-yl)carbamoyl)thiaz ol-5-sulfonimidamide

Exemplary LC-MS Number of Compound Structure IUPAC Name Column Eluents in the [M+H]+ post (R, R/S) or (S, R/S)-4-(2-hydroxypropan-2-yl) -N'-((3-Methyl-EtOH Chiralpak 1,2,3,5,6,7-hexa- in Hex 153 141b IC, 2*25 435 hydrodicyclopen- (0.1% cm, 5 um ta[ b,e]pyridin-8-FA)yl)carbamoyl)thiophene-2-sulfonimidamide (S,R/S) or (R,R/S)-4-(2-hydroxypropan-2-yl)-N'- ((3-Methyl-EtOH Chiralpak 1,2,3,5,6,7-hexa- in Hex 154 141a IC, 2*25,435 hydrodicyclopen- (0.1% cm, 5 um ta[b,e] pyridin-8-FA)yl)carbamoyl)thiophene-2-sulfonimidamide (R,R) or (R,S)-4-(2-hydroxypropan-2-EtOH CHIRAL-yl)-N'-((3-methyl - in PAK IG, 1,2,3,5,6,7-hexa-MTBE 155 141aa 2*25 cm 435 hydrodicyclopen- (NH 3 -(5 µm); from ta[b,e]pyridin-8-MeOH Ex 153 yl)carbamoyl)thiophene-10 mM) 2-sulfonimidamide (R,S) or (R,R)-4-(2-hydoxypropan-2-EtOH CHIRAL-yl)-N'-((3-methyl- in PAK IG, 1,2,3,5,6,7-hexa-MTBE 156 141ab 2*25 cm 435 hydrodicyclopen-(NH 3 -(5 µm); from ta[b,e]pyridin-8-MeOH Ex. 153 yl)carbamoyl)thiophene-10 mM) 2-sulfonimidami of (S,S) or (S,R)-4-(2-hydroxypropan-2-EtOH CHIRAL-yl)-N'-((3-methyl- in PAK IG, 1,2,3,5,6 ,7-hexa-MTBE 157 141ba 2*25 cm 435 hydrodicyclopen-(NH3-(5 µm); of ta[b,e]pyridin-8-MeOH Ex. 154 yl)carbamoyl)thiophene- 10 mM) 2-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents in the [M+H]+ post (S, R) or (S, S)-4-(2-hydroxypropan-2-EtOH CHIRAL-yl)- N'-((3-methyl- in PAK IG, 1,2,3,5,6,7-hexa-MTBE 158 141bb 2*25 cm 435 hydrodicyclopen-(NH3-(5 µm); do ta[b, e]pyridin-8-MeOH Ex. 154 yl)carbamoyl)thiophene- 10 mM) 2-sulfonimidamide (R, R/S) or (S, R/S)-4-(2-hydroxypropan-2-yl)- CHIRAL-EtOH 5-methyl-N'-((3-methyl-PAK IG, in Hex 159 104a 1,2,3,5,6,7-hexa-450 20*250 (0.1% hydrodicyclopen-mm , 5 a FA) ta[b,e]pyridin-8-yl)carbamoyl)thiazol-2-sulfonimidamide (S, R/S) or (R, R/S)-4-(2-hydroxypropan-2-yl )-CHIRAL-EtOH 5-methyl-N'-((3-methyl-PAK IG, in Hex 160 104b 1,2,3,5,6,7-hexa-450 20*250 (0.1% hydrodicyclopene) - mm, 5 um FA) ta[b,e]pyridin-8-yl)carbamoyl)thiazol-2-sulfonimidamide (S,S) or (S,R)-4-(hydroxymethyl)-2-(2-EtOH hydroxypropan-2-yl)-CHIRAL- in N'-((3-methyl-PAK IG, MTBE 161 168aa 1,2,3,5,6,7-hexa-466 2*25 cm (NH 3 -hydrodicyclopen- ( 5 um) MeOH ta[b,e]pyridin-8-10 mM) yl)carba moyl)thiazol-5-sulfonimidamide

Example Number- LC-MS of the compound- Structure Name IUPAC Column Eluents by the [M+H]+ post (S, R) or (S, S)-4-(hydroxymethyl)-2-(2-EtOH hydroxypropan-2 -yl)-CHIRAL- in N'-((3-methyl-PAK IG, MTBE 162 168ab 1,2,3,5,6,7-hexa-466 2*25 cm (NH 3 -hydrodicyclopen-(5 µm)) MeOH ta[b,e]pyridin-8-10 mM)yl)carbamoyl)thiazol-5-sulfonimidamide (R,S) or (R,R)-4-(hydroxymethyl)-2-(2-EtOH hydroxypropan-2 -yl)-CHIRAL- in N'-((3-methyl-PAK IG, MTBE 163 168ab 1,2,3,5,6,7-hexa-466 2*25 cm (NH 3 -hydrodicyclopen-(5 µm)) MeOH ta[b,e]pyridin-8-10 mM)yl)carbamoyl)thiazol-5-sulfonimidamide (R,R) or (R,S)-4-(hydroxymethyl)-2-(2-EtOH hydroxypropan-2 -yl)-CHIRAL- in N'-((3-methyl-PAK IG, MTBE 164 168bb 1,2,3,5,6,7-hexa-466 2*25 cm (NH 3 -hydrodicyclopen- (5 µm)) MeOH ta[b,e]pyridin-8-10 mM)yl)carbamoyl)thiazol-5-sulfonimidamide (R) or (S)-1-(difluoromethyl)-N'-((3,3-dimethyl-EtOH CHIRAL - 1,2,3,5,6,7-hexa- in Hex PAK IC, 165 122a hydrodicyclopen-(NH 3 .Me 425 2*25 cm, ta[b,e]pyridin-8-OH 8 5 umyl) carbamoyl)- 1H-mM) pyrazol-3-sulfonimidamide

Example Number- LC-MS of the compound- Structure Name IUPAC Column Eluents by the [M+H]+ post (S) or (R)-1-(difluoromethyl)-N'- ((3,3-dimethyl-EtOH CHIRAL - 1,2,3,5,6,7-hexa- in Hex PAK IC, 166 122b hydrodicyclopen-(NH 3 .Me 425 2*25 cm, ta[b,e]pyridin-8-OH 8 5 umyl) carbamoyl)-1H-mM) pyrazol-3-sulfonimidamide (S, R) or (S, S)-3-fluoro-5-(2-hydroxypropan-2-yl)-N'-((3-methyl-1st) and 2nd peaks at 167 103aa 1,2,3,5,6,7-hexa-CHIRAL ART Cellulo-453 hydrodicyclopentose-SB S, 2*25 ta[b,e]pyridin-8-cm, 5 µm, EtOH in yl)carbamoyl)thiophene-Hex (mM NH 3 .MeOH 8 2-sulfonimidamide); separated (S,S) or (S,R)-3- into individual fluoro-5-(2-dual isomers in CHIRAL-hydroxypropan-2-yl)-PAK IG, 2*25 cm, 5 N'-( (3-methyl-um, EtOH in 168 103ab 1,2,3,5,6,7-hexa-MTBE (NH 3 -MeOH 453 hydrodicyclopen- 10 mM) ta[b,e]pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide (R, R) or (R, S)-3- 3rd and 4th peaks in fluoro-5-(2-CHIRAL ART Celluhydroxypropan-2-yl)-lose-SB S, 2*25 N'-((3-methyl-cm, 5 µm, EtOH in 169 103ba 1,2,3,5,6,7-hexa-Hex (NH 3 .MeOH 8 453 hydrodicyclopen- mM); separated ta[b,e ]pyridin-8- in indiviyl)carbamoyl)thiophenedual isomers in CHIRAL-2-sulfonimidamide PAK IG, 2*25 cm, 5

Number Exemple- LC-MS of the compound- Structure Name IUPAC Column Eluents in the [M+H]+ post (R, S) or (R, R)-3-um, EtOH in fluoro-5-(2-MTBE ( NH 3 -MeOH hydroxypropan-2-yl)- 10 mM) N'-((3-methyl-170 103bb 1,2,3,5,6,7-hexa-453 hydrodicyclopenta[b,e]pyridin-8 -yl)carbamoyl)thiophene-2-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Cellu- in Hex ta[b,e]pyridin-8-171 102allose-SB, (NH 3 .Me 467 yl)carbamoyl)-3- 2*25 cm, OH 8 fluoro-5-(2-5 mM) hydroxypropan- 2-yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Celu-em Hex ta[b,e]pyridin-8-172 102blose-SB, (NH 3 .Me 467 yl)carbamoyl)-3- 2*25 cm, OH 8 fluoro-5-(2-5 mM) hydroxypropan-2 -yl)thiophene-2-sulfonimidamide (S) or (R)-3-fluoro-5-(2-hydroxypropan-2-yl)-N'-((1',5',6',7'-CHIRAL EtOH tetrahydro-2'H-ART Cellulose on Hex spiro[cyclopropane-101allose-SB, (NH 3 .Me 465 1.3'- 2*25 cm, OH 8 dicyclopent- 5 mM) ta[b ,e]pyridin]-8'-i l)carbamoyl)thiophene-2-sulfonimidamide

Exemplary Compound LC-MS Number IUPAC Name Column Eluents in the [M+H]+ post (R) or (S)-3-fluoro-5-(2-hydroxypropan-2-yl)-N'- ((1',5',6',7'-CHIRAL EtOH tetrahydro-2'H-ART Cellu- on Hex spiro[cyclopropane-174 101blose-SB, (NH3.Me 465 1.3'-2 *25 cm, OH 8 dicyclopen- 5 mM) ta[b,e]pyridin]-8'-yl)carbamoyl)thiophene-2-sulfonimidamide (S) or (R)-N'-((3,3- dimethyl-1,2,3,5,6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Cellulose Hex 175 125a ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 442 yl)carbamoyl) -4- 2*25 cm, OH 8 ((dimethylami-5 mM)no)methyl)benzenesulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5 ,6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Cellulose Hex 176 125b ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 442 yl)carbamoyl)-4- 2*25 cm, OH 8 ((dimethylamino-5 mM)no)methyl)benzenesulfonimidamide (R) or (S)-4-((dimethylamino-Hex CHIRAL-no)methyl)-N'-((5-(0.1% of PAK IG, 177 132a fluoro-2,4-di-DEA):Et 436 20*250 isopropylpyridin-3-OH=70: mm, 5 um yl)carbamoyl)benzen 30 osulfonimidamide

Exemplary Compound LC-MS Number Structure IUPAC Name Column Eluents in the [M+H]+ post (S) or (R)-4-((dimethylamino Hex CHIRAL-amino)methyl)-N'-(( 5-(0.1% PAK IG, 178 132b fluoro-2,4-di-DEA):Et 436 20*250 isopropylpyridin-3-OH=70: mm, 5 um yl)carbamoyl)benzen 30 ossulfonimidamide (S ) and (S, R, R) and (S, S, S)-N'-((3,5- 1st, 2nd, 3rd dimethyl-1,2,3,5,6,7-peak (three EtOH hexa-isomers) in Hex hydrodicyclopen-CHIRAL 179 131b (NH3.Me 449 ta[b,e]pyridin-8-ART Cellulo-OH 8yl)carbamoyl)-4-(2-lose-SB, mM) hydroxypropan-2 - 2*25 cm, yl)thiophene-2-5 a sulfonimidamide (R, S, S) and (R, R, 4th, 5th pi-R)-N'-((3,5-dimethyl-cos (two 1,2,3,5,6,7-hexa-EtOH isomers) hydrodicyclopen- in Hex

CHIRAL 180 131a ta[b,e]pyridin-8-(NH3.Me 449 ART Cellu-yl)carbamoyl)-4-(2-OH 8lose-SB, 2-mM hydroxypropan-25 cm, yl) thiophene-2-5 a sulfonimidamide (R, R, S) and (R, S, R)-N'-((3,5-dimethyl-6th peak 1,2,3,5,6,7-hexa- EtOH

CHIRAL hydrodicyclopen- on Hex ART Cellu- 181 131aab ta[b,e]pyridin-8-(NH3.Me 449lose-SB, yl)carbamoyl)-4-(2-OH 8 2*25 cm, hydroxypropan-2- mM) 5 um yl)thiophene-2-sulfonimidamide

Number Exem- LC-MS of the compound Structure IUPAC Name Column Eluents in the [M+H]+ rank (S, R, S) and (S, S, R) or (S, R, R) or (S, S,S)-N'-((3,5- 1st peak of dimethyl-1,2,3,5,6,7-EtOH Example hexa- in Hex 179; CHI-182 131c hydrodicyclopen-(NH3.Me 449)

RALPAK ta[b,e]pyridin-8-OH 8 IE, 2*25 yl)carbamoyl)-4-(2-mM) cm, 5 a hydroxypropan-2-yl)thiophene-2-sulfonimidamide (S, R, R) or (S, S, S) or (S, R, S) and (S, S, R)-N'-((3,5- 2nd peak of dimethyl-1,2,3,5,6 ,7- EtOH Example hexa- in Hex 179; CHI- 183 131d hydrodicyclopen- (NH3.Me 449

RALPAK ta[b,e]pyridin-8-OH 8 IE, 2*25 yl)carbamoyl)-4-(2-mM) cm, 5 a hydroxypropan-2-yl)thiophene-2-sulfonimidamide (S, S, S) or (S, R, S) and (S, S, R) or (S, R, R)-N'-((3,5-3rd peak of dimethyl-1,2,3,5,6 ,7- EtOH Example hexa- in Hex 179; CHI-184 131e hydrodicyclopen- (NH3.Me 449

RALPAK ta[b,e]pyridin-8-OH 8 IE, 2*25 yl)carbamoyl)-4-(2-mM) cm, 5 a hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ rank (R, S, S) or (R, R, 1st peak of R)-N'-((3.5 -dimethyl- Example 1,2,3,5,6,7-hexa-MeOH 180; CHI-hydrodicyclopen-(NH3.Me

RALPAK 185 131f ta[b,e]pyridin-8-OH 2 449 AD-H-yl)carbamoyl)-4-(2-mM) in TC001 hydroxypropan-2-CO 2 SFC, 2*25 yl)thiophene-2- cm, 5 a sulfonimidamide (R, R, R) or (R, S, 2nd peak S)-N'-((3,5-dimethyl- resulted in 1,2,3,5,6,7-hexane) Exem-MeOH hydrodicyclopentyl.180 (NH3.Me 186 131g ta[b,e]pyridin-8-CHIRAL-OH 2449yl)carbamoyl)-4-(2-PAK AD-mM) in hydroxypropan-2-H -TC001 CO2 yl)thiophene-2-SFC, 2*25 cm sulfonimidamide, 5 µm (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopen-CHIRAL- 30% ta[b,e]pyridin-8-PAK IG, MeOH and 187 121a 480 yl)carbamoyl)-4- 20*250 70% (hydroxymethyl)-2-(2-mm , 5 a CO 2 hydroxypropan-2-yl)thiazol-5-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopen- CHIRAL- 30% ta[b,e]pyridin-8-PAK IG, MeOH and 188 121b 480 yl)carbamoyl)-4- 20*250 70% (hydroxymethyl)-2-(2-mm, 5um CO 2 hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Example Number- LC-MS of the compound Structure Name IUPAC Column Eluents by the [M+H]+ post (S) or (R)-N'-((3,3-dimethyl-1,2,3,5, 6,7-hexa-CHIRAL EtOH hydrodicyclopen-ART Cellu- on Hex 189 169a ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 463 yl)carbamoyl)-4-(2-2*25 cm , OH 8 hydroxypropan-2-yl)-5 mM) 5-methylthiophene-2-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6, 7-hexa-CHIRAL EtOH hydrodicyclopen-ART Cellu- on Hex 190 169b ta[b,e]pyridin-8-lose-SB, (NH 3 .Me 463 yl)carbamoyl)-4-(2-2*25 cm, OH 8 hydroxypropan-2-yl)-5 mM) 5-methylthiophene-2-sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL - in Hex ta[b,e]pyridin-8-PAK IG, 191 119a (NH 3 .Me 389 yl)carbamoyl)-1- 20*250 OH 8 isopropyl-1H-mm, 5 mM) pyrazol-3-sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IG, 192 119b ( NH3.Me 389 yl)carbamoyl)-1- 20*250 OH 8 isopropyl-1H-mm, 5 mM) pyrazol-3-sulfonimidamide

Number Exemple- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ rank (R) or (S)-N'- ((1,2,3,5,6,7-hexa- hydrodicyclopen-EtOH CHIRAL-ta[b,e]pyridin-8- in Hex PAK IF, 193 118a yl)carbamoyl)-4-(2-(NH 3 .Me 466 2*25 cm, hydroxyethyl)-2-(2- OH 8 5 a hydroxypropan-2-mM)yl)thiazol-5-sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexahydrodicyclopen-EtOH CHIRAL-ta [b,e]pyridin-8- in Hex PAK IF, 194 118b yl)carbamoyl)-4-(2-(NH 3 .Me 466 2*25 cm, hydroxyethyl)-2-(2-OH 8 5 a hydroxypropan- 2-mM)yl)thiazol-5-sulfonimidamide (S,S) or (S,R)--4-((dimethylamino)methyl)-N'-((3-EtOH CHIRAL-methyl-1,2 ,3,5,6,7- in Hex PAK IG, 195 134aa hexa-(NH3.Me 428 2*25 cm hydrodicyclopen-OH 8 (5 µm) ta[b,e]pyridin-8-mM)yl)carbamoyl )benzenesulfonimidamide (S, R) or (S, S)-4-((dimethylamino)methyl)-N'-((3-EtOH CHIRAL-methyl-1,2,3,5,6,7- in Hex PAK IG, 196 134ab hexa-(NH3.Me 428 2*25 cm hydrodicyclopen-OH 8 (5 µm) ta[b,e]pyridin-8-mM)yl)carbamoyl)benzenesulfonimidamide

Exemplary Compound LC-MS Number Structure IUPAC Name Column Eluents in the [M+H]+ post (R, R) or (R, S)-4-((dimethylamino)methyl)-N'-( (3-CHIRAL EtOH methyl-1,2,3,5,6,7-ART Cellu- on Hex 197 134ba hexalose-SB, (NH 3 .Me 428 hydrodicyclopen- 2*25 cm, OH 8 ta[b, e]pyridin-8-5 mM) yl)carbamoyl)benzenesulfonimidamide (R,S) or (R,R)-4-((dimethylamino)methyl)-N'-((3-CHIRAL EtOH methyl) 1,2,3,5,6,7-ART Cellu- on Hex 198 134bb hexalose-SB, (NH3.Me 428 hydrodicyclopen- 2*25 cm, OH 8 ta[b,e]pyridin-8-5 one mM) yl)carbamoyl)benzenesulfonimidamide (S) or (R)-N'-((3-ethyl-2-methyl-6,7-diCHIRAL EtOH hydro-5H-ART Cellu- in Hex cyclopenta[b) ]pyridin-199 117allose-SB, (NH 3 .Me 424 4-yl)carbamoyl)-2-(2-2*25 cm, OH 8 hydroxypropan-2-5 mM) yl)thiazol-5-sulfonimidamide (R ) or (S)-N'-((3-ethyl-2-methyl-6,7-di-CHIRAL EtOH hydro-5H-ART Cellu- in Hex cyclopenta[b]pyridin-117blose-SB, (NH3 .Me 424 4-yl)carbamoyl)-2-(2-2*25 cm, OH 8 hydroxypropan-2-5 mM) yl)thiazol-5-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ rank (S) or (R)-1- Isopropyl-N'- ((1',5',6',7 '-Tetra-EtOH hydro-2'H-CHIRAL-(NH 3 -spiro[cyclopropane-PAK AS-201 172a MeOH 2 415 1,3'-dicyclo-H, 2*25 mM) in penta[b,e]pyridin ]-8'-cm (5 µm) CO 2 yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (R) or (S)-1-Isopropyl-N'-((1',5',6',7 '-Tetra-EtOH hydro-2'H-CHIRAL-(NH 3 -spiro[cyclopropane-PAK AS-202 172b MeOH 2 415 1,3'-dicyclo-H, 2*25 mM) in penta[b,e]pyridin ]-8'-cm (5 µm)CO 2 yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa- EtOH CHIRAL- hydrodicyclopen- in Hex PAK IG, 203 173a ta[b,e]pyridin-8-(NH3.Me 405 2*25 cmyl)carbamoyl)-4-OH 8 (5 µm) isopropylthiophene-2-mM) sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexa-EtOH CHIRAL-hydrodicyclopen- in Hex PAK IG, 204 173b ta[b,e]pyridin-8- (NH3.Me 405 2*25 cmyl)carbamoyl)-4-OH 8 (5 µm) isopropylthiophene-2-mM)sulfonimidamide

Exemplary LC-MS Number of Compound Structure IUPAC Name Column Eluents in the [M+H]+ post (R, R) or (R, S)-N'- ((3-fluoro-1,2,3, 5,6,7-hexa-CHIRAL-EtOH hydrodicyclopen-PAK IC, in Hex 205 183a ta[b,e]pyridin-8-440 2*25 cm, (0.1% yl)carbamoyl)-2-( 2- 5 a FA)hydroxypropan-2-yl)thiazol-5-sulfonimidamide (S,S) or (S,R)-N'-((3-fluoro-1,2,3,5,6,7- hexa-CHIRAL-EtOH hydrodicyclopen-PAK IC, in Hex 206 183b ta[b,e]pyridin-8-440 2*25 cm, (0.1% yl)carbamoyl)-2-(2-5um FA) hydroxypropan-2-yl)thiazol-5-sulfonimidamide (R,S) or (R,R)-N'-((3-fluoro-1,2,3,5,6,7-hexa-CHIRAL-EtOH hydrodicyclopen - PAK IC, in Hex 207 183c ta[b,e]pyridin-8- 440 2*25 cm, (0.1% yl)carbamoyl)-2-(2-5um FA)hydroxypropan-2-yl) thiazol-5-sulfonimidamide (S,R) or (S,S)-N'-((3-fluoro-1,2,3,5,6,7-hexa-CHIRAL-EtOH hydrodicyclopen-PAK IC, in Hex 208 183d ta[b,e]pyridin-8- 440 2*25 cm, (0.1% yl)carbamoyl)-2-(2-5um FA)hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents in the [M+H]+ post (S) or (R)-2-(2-hydroxypropan-2-yl)-EtOH N'-((3) -isopropyl-2-CHIRAL- in methyl-6,7-dihydro-PAK IE, 209 116a MTBE 438 5H-cyclopenta[b]pyri-2*25 cm, (0.1% din-4-yl) carbamoyl)-5 a FA) thiazol-5-sulfonimidamide (R) or (S)-2-(2-hydroxypropan-2-yl)-EtOH N'-((3-isopropyl-2-CHIRAL- in methyl-6 ,7-dihydro-PAK IE, 210 116b MTBE 438 5H-cyclopenta[b]- 2*25 cm, (0.1% pyridin-4-5um FA)yl)carbamoyl)thiazol-5-sulfonimidamide ( R) or (S)-4-(2-hydroxypropan-2-yl)-N'-((1',5',6',7'-tetra-EtOH CHIRAL-OH hydro-2'H-spiro- in Hex PAK IG, 211 114a HN N [cycloprop-pane-1,3'-(NH3.Me 447

N 2*25 cm

S *SOO dicyclopen-OH 8 H 2 N (5 µm) ta[b,e]pyridin]-8'-mM) yl)carbamoyl)thiophene-2-sulfonimidamide (S) or (R)-4-(2-hydroxypropan- 2-yl)-N'-((1',5',6',7'-tetra-EtOH CHIRAL-hydro-2'H-spiro- in Hex PAK IG, 212 114b [cycloprop-pan-1,3 '-(NH3.Me 447 2*25 cm dicyclopen-OH 8 (5 µm) ta[b,e]pyridin]-8'-mM) yl)carbamoyl)thiophene-2-sulfonimidamide

Example Number- LC-MS of the compound- Structure Name IUPAC Column Eluents by the [M+H]+ post (S) or (R)-N'-((2-cyclopropyl-3-methyl-CHIRAL EtOH 6,7- dihydro-5H-ART Cellu- in Hex cyclopenta[b]pyridin-124lose-SB, (NH 3 .Me 436 4-yl)carbamoyl)-2-(2-2*25 cm, OH 8 hydroxypropan-2 - 5 mM) yl)thiazol-5-sulfonimidamide (R) or (S)-N'-((2-cyclopropyl-3-methyl-CHIRAL EtOH 6,7-dihydro-5H-ART Cellu- in Hex cyclopenta[b]pyridin-214 124blose-SB, (NH3.Me 436 4-yl)carbamoyl)-2-(2-2*25 cm, OH 8 hydroxypropan-2-5 mM)yl)thiazol-5- sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IC, 215 154a (NH3.Me 422 yl)carbamoyl)-2-(2-2*25 cm, OH 8 hydroxypropan-2-5 mM)yl)thiazol-4-sulfonimidamide (S) or (R)-N'-(( 1,2,3,5,6,7-hexa-EtOH hydrodicyclopen-CHIRAL- in Hex ta[b,e]pyridin-8-PAK IC, 216 154b (NH3.Me 422 yl)carbamoyl)-2-(2 - 2*25 cm, OH 8 hydroxypropan-2- 5 mM) yl)thiazol-4-sulfonimidamide (R) or (S)-4-((dimethylami-EtOH no)methyl) -N'-CHIRAL- in ((1,2,3,5,6,7-hexa-PAK IE, MTBE 217 120a hydrodicyclopen-428 2*25 cm, (NH 3 -ta[b,e]pyridin-8- 5 a MeOH yl)carbamoyl)-N-10 mM) methylbenzenesulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ post (S) or (R)-4-((dimethylamino-EtOH no)methyl)-N'-CHIRAL- in ( (1,2,3,5,6,7-hexa-PAK IE, MTBE 218 120b hydrodicyclopent-428 2*25 cm, (NH 3 -ta[b,e]pyridin-8-5 a MeOH yl)carbamoyl)- N-10 mM) methylbenzenesulfonimidamide (R) or (S)-2-(2-hydroxypropan-2-yl)-N'-((2-phenyl-6,7-di-CHIRAL-EtOH hydro-5H- PAK IF, in Hex 219 142a 458 cyclopenta[b]pyridin-2*25 cm, (0.1% 4-yl)carbamoyl)-5um FA)thiazol-5-sulfonimidamide (S) or (R)-2 -(2-hydroxypropan-2-yl)-N'-((2-phenyl-6,7-di-CHIRAL-EtOH hydro-5H-PAK IF, in Hex 220 142b 458 cyclopenta[b]pyridin-2*25 cm, (0.1% of 4-yl)carbamoyl)-5um FA)thiazol-5-sulfonimidamide (S) or (R)-2-(2-hydroxypropan-2-yl)-CHIRAL N'-(( 3-Methyl-2-phenyl-ART Cellu-EtOH 6,7-dihydro-5H-lose-SB in Hex 221 143a 472 cyclopenta[b]pyridin-S-5um, (0.1% of 4-2 *25 cm, FA)yl)carbamoyl)thiazol-5a 5-sulfonimidamide (R) or (S)-2-(2-hydroxypropan-2-yl)-CHIRAL N'-((3-methyl-2-phenyl - ART Cellulo-EtOH 6,7-dihydro-5H-lose-SB in Hex 222 143b 472 cyclopenta[b]pyridin-S-5um, (0.1% 4-yl)carbamoyl)- 2*25 cm , FA) thiazole-5-5 a sulfonimamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ post (R, R) or (R, S)-1-(difluoromethyl)-N'- 1st peak EtOH ((3 -methyl- Column, in 1,2,3,5,6,7-hexa-CHIRAL-MTBE 223 184a hydrodicyclopen-411 PAK IG, (NH 3 -ta[b,e]pyridin-8- 20*250 MeOH yl) carbamoyl)-1H-mm, 5 to 10 mM) pyrazol-3-sulfonimidamide (S,S) or (S,R)-1-(difluoromethyl)-N'-((3-methyl-Eluted as a 1,2 224 184b hydrodicyclopen- 411 CHIRAPAK ta[b,e]pyridin-8-IG, 20*250 mm, 5 yl)carbamoyl)-1H-um. EtOH in pyrazol-3-MTBE (10 mM NH 3 -MeOH sulfonimidamide). (R, S) or (R, R)-1- Separated into individual (difluoromethyl)-N'-isomers ((3-methyl-als in CHIRAL-1,2,3,5,6,7-hexa- PAK IG, 2*25 cm (5 225 184c hydrodicyclopen-411 µm), EtOH in Hex ta[b,e]pyridin-8-(8 mM NH 3 -MeOH)yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide ( S, R) or (S, S)-1-(difluoromethyl)-N'-EtOH ((3-Methyl-Column, in 1,2,3,5,6,7-hexa-CHIRAL-

MTBE 226 184d hydrodicyclopen-PAK IG, 411 (NH3-ta[b,e]pyridin-8-20*250 MeOH yl)carbamoyl)-1H-mm, 5 to 10 mM) pyrazol-3-sulfonimidamide

Example Number- LC-MS of the compound- Structure Name IUPAC Column Eluents by the [M+H]+ post (R) or (S)-N'-((2-cyclopropyl-3-methyl-6,7-di- hydro-5H-CHIRAL IPA in cyclopenta[b]pyridin-ART Cellulo-Hex 227 174a 4-yl)carbamoyl)-3-lose-SB, (NH 3 .Me 453 fluoro-5-(2-2*25 cm, OH 8 hydroxypropan-2-5 mM)yl)thiophene-2-sulfonimidamide (S) or (R)-N'-((2-cyclopropyl-3-methyl-6,7-dihydro-5H-CHIRAL IPA in cyclopenta[b]pyridin-ART Cellu-Hex 228 174b 4-yl)carbamoyl)-3-lose-SB, (NH 3 .Me 453 fluoro-5-(2-2*25 cm, OH 8 hydroxypropan-2-5um mM) yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((2-cyclopropyl-3-methyl-CHIRAL IPA in 6,7-dihydro-5H-ART Celu-Hex cyclopenta[b) ]pyridin-229 175allose-SB, (NH 3 .Me 435 4-yl)carbamoyl)-4-(2-2*25 cm, OH 8 hydroxypropan-2-5 mM) yl)thiophene-2-sulfonimidamide (S ) or (R)-N'-((2-cyclopropyl-3-methyl-CHIRAL IPA in 6,7-dihydro-5H-ART Cellu-Hex cyclopenta[b]pyridin-230 175blose-SB, (NH 3 .Me 435 4-yl)carbamoyl)-4-(2-2*25 cm, OH 8 hydroxypropan-2-5 mM) yl)thiophene -2- sulfonimidamide

Example Number- LC-MS of the compound- Structure IUPAC Name Column Eluents by the [M+H]+ post (R) or (S)-1-(difluoromethyl)-N'- ((1',5',6' ,7'-tetrahydro-2'H-MeOH(N CHIRAL-spiro[cyclopro-H3-PAK IG, 231 180a pano-1,3'-MeOH 2 423 20*250 dicyclopen- mM) in mm, 5 µm ta[b,e]pyridin]-8'-CO 2 yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (S) or (R)-1-(difluoromethyl)-N'-((1',5', 6',7'-tetrahydro-2'H-MeOH(N CHIRAL-spiro[cyclopro-H3-PAK IG, 232 180b pano-1,3'-MeOH 2 423 20*250 dicyclopen- mM) in mm, 5 a ta[b,e]pyridin]-8'-CO2 yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide # The amount of NH3 in this chiral chromatographic solvent and similar solvents was adjusted by adding 2M NH3 in methanol to the desired concentration of NH3. In this case, the resulting concentration of NH3 in methanol is 8 mM.

[002598] Single crystal X-ray crystallographic analysis was performed on compound 162bb (Example 107 shown in Table 23 above). Figure 1 shows ball-and-stick models of the asymmetric unit containing two crystallographically independent molecules of compound 162bb, with hydrogen atoms omitted for clarity. Table M below shows fractional atomic coordinates of compound 162bb. The X-ray crystal structure data of compound 162bb show the (R) configuration at both the sulfur and carbon stereocenters.

Table 25. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Shift Parameters (Å2×103) for Example 107. Ueq is defined as 1/3 of the trace of the orthogonized UIJ tensor.

Atom xyz U(eq) S4 5075(6) 4544(8) 4537(3) 36.8(19) S2 4781(6) 4698(9) -473(3) 43(2) S1 7558(7) 5846( 10) -529(3) 50(2) S3 2293(7) 5663(9) 4517(3) 46(2) O2 4520(16) 6060(20) -694(8) 39(5) O5 5510(15 ) 3200(20) 4347(7) 31(4) O3 4619(17) 5920(20) 674(8) 45(5) N3 4140(18) 4020(20) 66(9) 25(5) O6 5356( 18) 3350(20) 5721(9) 50(5) N9 5338(18) 5480(30) 6075(9) 36(6) N8 5550(20) 5180(30) 5117(11) 48(7) N4 4450 (20) 3850(30) 1039(11) 51(7) O4 -270(20) 6350(30) 4492(10) 57(6) N7 5257(19) 5700(30) 4048(10) 37(6) O1 10130(20) 6580(30) -616(10) 66(7) N2 4410(20) 3530(30) -970(9) 32(5) C00H 5460(20) 4710(30) 5620(11) 31 (6) C20 1070(20) 4520(30) 4713(11) 35(7) N10 5083(19) 4460(20) 7857(6) 75(9) C32 6064(18) 3890(20) 7545(8) 66(10) C33 6147(16) 4230(20) 6957(8) 46(8) C26 5250(17) 5130(20) 6679(6) 41(7) C27 4269(16) 5700(20) 6991(8) ) 46(8) C31 4186(16) 5360(20) 7579(8) 47(8) N1 8450(20) 3680(30) 38(10) 40(6) C2 6540(30) 4700(40) -317 (13) 47(7) N6 1480(20) 3260(30) 4781(10) 43(6) C7 4370(30) 4560(40) 561( 14) 54(8)

Fractional Atomic Coordinates (×104) and Equivalent Isotropic Shift Parameters (Å2×103) for Example 107. Ueq is defined as 1/3 of the trace of the orthogonized UIJ tensor.

Atom xyz U(eq) C4 10220(20) 5300(30) -295(12) 38(7) C16 7300(30) 5850(40) 2595(15) 59(9) C21 3350(30) 4350(40) 4584(13) 46(8) C14 5804(16) 4870(20) 1845(8) 45(8) C8 4666(18) 4160(20) 1669(7) 43(8) C9 3784(16) 3830(30) ) 2079(9) 66(10) C13 4039(19) 4200(30) 2665(8) 81(12) N5 5180(20) 4910(30) 2841(7) 78(9) C15 6059(17) 5240( 30) 2431(9) 83(12) C18 7080(30) 5340(40) 1585(13) 46(8) C22 2820(20) 3160(40) 4759(12) 37(7) C25 -750(30) 4770(50) 5293(15) 63(9) C6 10910(30) 5480(50) 336(16) 69(10) C34 7230(30) 3470(50) 6749(15) 66(10) C5 10840(30) ) 4200(50) -671(17) 74(11) C30 3160(40) 6000(50) 7827(19) 92(13) C28 3190(30) 6640(50) 6797(16) 70(11) C23 - 290(30) 4940(40) 4703(13) 49(8) C3 7110(30) 3580(40) -17(12) 43(8) C17 7830(40) 6370(50) 2016(18) 88(13) ) C36 7060(30) 2850(50) 7758(16) 70(11) C35 7990(40) 2950(50) 7343(17) 82(12) C1 8870(20) 4850(30) -219(12) 39 (7) C24 -1130(30) 4170(50) 4203(16) 71(11) C12 2860(40) 3740(60) 3000(20) 92(14) C29 2320(40) 6600(50) 7354(17) ) 79(12) C10 2690(40) 2920( 50) 1935(19) 89(13) C37 7650(60) 2820(80) 8380(30) 160(30) C11 2050(50) 3380(70) 2530(20) 112(17)

Fractional Atomic Coordinates (×104) and Equivalent Isotropic Shift Parameters (Å2×103) for Example 107. Ueq is defined as 1/3 of the trace of the orthogonized UIJ tensor.

Atom x y z U(eq) C19 7290(50) 7110(60) 3030(20) 113(17) Example 233 (Compound 652)

N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(hydroxymethyl)-1-isopropyl- 1H-pyrazol-3-sulfonimidamide (Scheme I) Examples 234 (Compound 652b) and 235 (Compound 652a)

(R)- and (S)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5 -(hydroxymethyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide

Step 1: N-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa- hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide

[002599] To a stirred solution of N'-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide (1.0 g, 2. 2 mmol) in THF (50 ml) in a 100 ml 3-necked round bottom flask under nitrogen, t-BuOK (493 mg, 4.4 mmol) was added in portions at 0 °C. The resulting solution was stirred for 15 min at 0 °C. To the above mixture, 2,2,2-trichloroethyl (3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (830 mg, 2.2 mmol) in THF (5 ml) by dripping at 0 °C. The resulting mixture was stirred overnight at RT. The resulting solution was then quenched with water (5 ml). The mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (20:1). This resulted in 400 mg (27%) of the title compound as an off-white solid. MS-ESI: 675 (M+1). Step 2: N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(hydroxymethyl)-1 - isopropyl-1H-pyrazol-3-sulfonimidamide

[002600] To a stirred solution of N-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-N'-((3,3-dimethyl-1,2,3,5,6 ,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide (400 mg, 0.59 mmol) in THF (20 mL) in a vial of 100 ml round bottom, HF-pyridine (70% by weight, 50 mg, 1.77 mmol) was added dropwise at 0°C. The reaction solution was stirred for 2 h at RT. The resulting mixture was concentrated in vacuo. The crude product was purified by prep HPLC. using the following conditions: Column XBridge Prep C18 OBD 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 9% B to 36% B for 7 min; UV 254/210 nm; Rt: 7.13 min. This resulted in 200 mg (75.6%) of Example 233 as a white solid. MS-ESI: 447 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 6.70 (s, 1H), 4.79-4.74 (m, 1H), 4.66 (s, 2H), 2.95 (t, J = 7.6 Hz, 2H), 2.86-2.76 (m, 4H), 2.16-2.03 (m, 2H), 1.96 (t, J = 7.2 Hz, 2H), 1.52 (d, J = 6.6 Hz, 3H), 1.51 (d, J = 6.6 Hz, 3H), 1.27 (s, 6H). Step 3: Chiral Resolution

[002601] Example 233 (200 mg) was separated by preparatory chiral HPLC with the following conditions: Column: CHIRALPAK AS, 2*25 cm (5 µm); Mobile Phase A: CO2, Mobile Phase B: EtOH (2 mM NH3-MeOH); Flow rate: 40 ml/min; Gradient: 20% B; 220 nm; RT1:4.54; RT2:6.29; Injection Volume: 2.5 ml; Number of Rounds:

10. This resulted in 81 mg of Example 234 followed by 75 mg of Example 235, both as white solids.

[002602] Example 234: MS-ESI: 447 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 6.70 (s, 1H), 4.79-4.72 (m, 1H), 4.66 (s, 2H), 2.95 (t, J = 7.6 Hz, 2H), 2.84-2.73 (m, 4H), 2.16-2.03 (m, 2H), 1.96 (t, J = 7.3 Hz, 2H), 1.52 (d, J = 6.6 Hz, 3H), 1.51 (d, J = 6.6 Hz, 3H), 1.27 (s, 6H).

[002603] Example 235: MS-ESI: 447 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 6.70 (s, 1H), 4.81-4.74 (m, 1H), 4.66 (s, 2H), 2.95 (t, J = 7.6 Hz, 2H), 2.86-2.75 (m, 4H), 2.14-2.05 (m, 2H), 1.96 (t, J = 7.3 Hz, 2H), 1.52 (d, J = 6.6 Hz, 3H), 1.51 (d, J = 6.6 Hz, 3H), 1.27 (s, 6H). Example 236 (Compound 695) N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl )-3-methylthiophene-2-sulfonimidamide (Scheme II)

[002604] Step 1: N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5- (2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide

[002605] To a stirred solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide (150mg, 0.43mmol) in THF (10ml) in a 50 ml round bottom flask under nitrogen, NaH (60% by weight, dispersion in mineral oil, 34.4 mg, 0.86 mmol) was added at 0 °C. The resulting solution was stirred for 10 min at RT. Then, 2,2,2-trichloroethyl (1,2,2,2-trichloroethyl (150 mg, 0.43 mmol) in THF (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) 5 ml) was added dropwise at 0°C into the mixture. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 1.0 ml of water. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 230 mg (97.4%) of the title compound as a yellow solid. MS-ESI: 549 (M+1). Step 2: N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-3 -methylthiophene-2-sulfonimidamide

[002606] To a stirred solution of N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)- 5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide (230 mg, 0.42 mmol) in THF (10 ml) in a 50 ml round bottom flask, TBAF (110 mg , 0.42 mmol) in portions at RT. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by prep HPLC. using the following conditions: XBridge Prep OBD C18 column, 30x150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (20% to 60% in 7 min); 254/210 nm; RT: 6.13 min. This resulted in 100 mg (55%) of Example 236 as a white solid. MS-ESI: 435 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.56 (1, s, 2H), 6.81 (s, 1H), 5.67 (s, 1H), 2 .82-2.68 (m, 8H), 2.37 (s, 3H), 2.00-1.92 (m, 4H), 1.48 (s, 3H), 1.47 (s, 3H ). Table 33. The examples in the following table were prepared using conditions similar to those described in Example 236 and Scheme II from appropriate starting materials. Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ N-((1,2,3,5,6,7-hexa- HO O NH O hydrodicyclopen- Sta[b,e ]pyridin-8-NN yl)carbamoyl)-4-(1- 237 643 NHN 466 SH hydroxyethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-

HO sulfonimidamide 2-(1,2-Di-H 2 N hydroxypropan-2-yl)-

N S O O N'-((3,3-dimethyl-

S N 1,2,3,5,6,7-hexa-238 201 HN 466 HO hydrodicyclopent-

N ta[b,e]pyridin-8-

HO yl)carbamoyl)thiazol-5-sulfonimidamide 5-(1,2-Dihydroxypropan-2-yl)-O H N'-((3,3-dimethyl-

F N

The 1,2,3,5,6,7-hexa-

S N 239 640 hydrodicyclopen- 483 S NH 2 N ta[b,e]pyridin-8-HO yl)carbamoyl)-3-

HO fluorothiophene-2-sulfonimidamide

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ 2-(1,2-Dihydroxypropan-2-yl)-H N'-((3-methyl-2-

O N N N (trifluoromethyl)-6,7-di- 240 605 S 480 N hydro-5H-NH 2 O F S cyclopenta[b]pyridin-4-

OH F (Fil)carbamoyl)thiazole-5-

HO sulfonimidamide (R, RS) or (S, RS) 2-(-1,2-dihydroxypropan-H 2 N F 2-yl)-N'-((3-methyl-2-

O F S O (trifluoromethyl)-6,7-di-

N N F S hydro-5H- 241 605f HN N 480 cyclopenta[b]pyridin-4- * HO yl)carbamoyl)thiazol-5-

HO sulfonimidamide (from Intermediate 117A) (S, RS) or (R, RS) 2-(-1,2-di-H 2 N hydroxypropan-2-yl)-

The F F N'-((3-methyl-2-

S O N N F (trifluoromethyl)-6,7-di- 242 605a S hydro-5H- 480

HN N * cyclopenta[b]pyridin-4-HO yl)carbamoyl)thiazol-5-HO sulfonimidamide (from Intermediate 117B) 3-Chloro-N'-((1,2,3,5,6, 7-hexahydrodicyclopent-Clta[b,e]pyridin-8- 243 691 HN N 455 N yl)carbamoyl)-5-(2-SSO hydroxypropan-2-

OH O H2N yl)thiophene-2-sulfonimidamide

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ 4-Chloro-N'- ((1,2,3,5,6,7-hexahydrodicyclopen-Cl HN N ta[ b,e]pyridin-8- 244 688 455 N yl)carbamoyl)-5-(2-SSO hydroxypropan-2-

OH O H2N yl)thiophene-2-sulfonimidamide N'-((2-cyclopropyl-3-methyl-6,7-dihydro-5H-

F H cyclopenta[b]pyridin-4-

N N 245 676 F N N yl)carbamoyl)-1-411

N S (difluoromethyl)-1H-

O H2N O pyrazol-3-sulfonimidamide 4-(2-hydroxypropan-2-yl)-N'-((3-methyl-2-(1-methylcyclopropyl)-6,7-

HO 246 669 HN N dihydro-5H- 449 N cyclopenta[b]pyridin-4-

S S O O yl)carbamoyl)thiophene-H 2 N 2-sulfonimidamide N'-((2,6-dicyclopropyl-3,5-dimethylpyridin-4-HO yl)carbamoyl)-4-(2- 247 612 HN N 449 hydroxypropan-2-

NSSO yl)thiophene-2-Osulfonimidamide H 2 N 2-(1,2-Dihydroxypropan-2-yl)-N'-((3-isopropyl-2-methyl-6,7-dihydro- 5H-454 cyclopenta[b]pyridin-4-yl)carbamoyl)thiazol-5-sulfonimidamide

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ 4-(2-hydroxypropan-2-yl)-N'-((2-(2,2,2-trifluoroethyl)-6 ,7-di-249 607 hydro-5H- 463 cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide Example 250 (Compound 665) N'-((3,3-dimethyl-1,2, 3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-4-((methylamino)methyl)thiazol-5-sulfonimidamide (Scheme III)

[002607] Step 1: 4-(Bromomethyl)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl )-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002608] To a stirred solution of N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4- (hydroxymethyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (800 mg, 1.68 mmol) in THF (20 ml) in a 100 ml 3-necked round bottom flask under nitrogen, Phosphorus tribromide (676 mg, 2.52 mmol) was added dropwise at 0°C. The resulting solution was stirred for 4 h at RT. The solution was slowly poured into water/ice (20 ml). The solution

The resulting mixture was extracted with 3x100 ml of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. This resulted in 540 mg (60%) of the crude title compound as an off-white solid. MS-ESI: 542/544 (M+1). Step 2: N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan- 2-yl)-4-((methylamino)methyl)thiazol-5-sulfonimidamide

[002609] To a stirred solution of 4-(bromomethyl)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl )carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (500 mg, 0.92 mmol) in THF (10 mL) in a round bottom flask, methanamine in THF ( 2M, 2.31 ml, 4.62 mmol) by dripping at RT. The resulting solution was stirred for 4 h at 50 °C. The reaction was quenched with water (10 ml). The resulting solution was extracted with 3x50 ml of ethyl acetate, and the organic layers were combined and dried over anhydrous Na2SO4. Then, the organic phase was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). The crude product was further purified by prep. with the following conditions: Column XBridge Prep C18 OBD 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 10% B to 24% B for 7 min; 254/210 nm; Rt: 6.52 min. This resulted in 200 mg (44%) of Example 250 as a yellow solid. MS-ESI: 493 (M+1). Example 251 (Compound 693) N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-

methoxypropan-2-yl)thiazol-5-sulfonimidamide (Scheme IV) Step 1: (N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl tert-butyl)-2-(2-methoxypropan-2-yl)thiazol-5-sulfonimidoyl)carbamate

[002610] To a stirred solution of tert-butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfanoylidene)carbamate (500 mg, 1.49 mmol) in THF (10 ml) in a 100 ml round bottom flask under nitrogen was added NaH (60 wt%, mineral oil dispersion, 71.5 mg, 1.79 mmol) at 0 °C. The resulting solution was stirred for 10 min at RT. Then, 2,2,2-Trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (521 mg, 1.49 mmol) in THF ( 5 ml) was added dropwise into the solution at 0°C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 ml of water. The resulting solution was extracted with 3x50 ml of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. This resulted in 400 mg (50%) of the title compound as a yellow solid. MS-ESI: 536 (M+1). Step 2: N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-methoxypropan-2-yl)thiazol- 5-sulfonimidamide

[002611] A stirred solution of (N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-methoxypropan-2- tert-butyl yl)thiazol-5-sulfonimidoyl)carbamate (300mg, 0.56mmol) in HCl/dioxane (4M, 20ml) was stirred for 15h at RT. The resulting mixture was concentrated in vacuo. The crude product was purified by prep HPLC. under the following conditions: XBridge Prep OBD C18 column

30×150 mm 5 µm; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 10% B to 20% B over 9.5 min; 254/210 nm; Rt: 7.32. This resulted in 130 mg (54%) of Example 251 as a white solid. MS-ESI: 436 (M+1). 1 H NMR (300 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.97 (sl, 2H), 3.25 (s, 3H), 2, 87-2.78 (m, 4H), 2.73-2.68 (m, 4H), 1.98-1.93 (m, 4H), 1.56 (s, 6H). Example 252 (Compound 645) 3-Fluoro-5-(2-hydroxypropan-2-yl)-N'-((2-isopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin -4-yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme V)

[002612] Step 1: N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)-N'-((2-isopropyl-3-methyl-6,7-dihydro -5H-cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide

[002613] To a stirred solution of N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (300 mg, 0.85 mmol) in THF (20 ml ) in a 50 ml round bottom flask under nitrogen, NaH (60% by weight, mineral oil dispersion, 102 mg, 2.56 mmol) was added at 0 °C. The resulting solution was stirred for 15 min at RT. 2,2,2-Trichloroethyl (2-isopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]-pyridin-4-yl)carbamate (310 mg, 0.85 mmol) in THF (5 ml)

was added dropwise to the solution. The resulting solution was stirred overnight at RT and quenched with water (2.0 ml). The resulting solution was concentrated in vacuo to obtain 580 mg of the title compound as an off-white crude solid which was used in the next step without further purification. MS-ESI: 569 (M+1). Step 2: 3-Fluoro-5-(2-hydroxypropan-2-yl)-N'-((2-isopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2-sulfonimidamide

[002614] The crude product (580 mg) of N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)-N'-((2-isopropyl-3-methyl-6, 7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide was run on a TLC and using DCM/MeOH=10:1 to maintain Rf = 0, 3~0.6, then the product was left on TLC overnight at RT. The TBS group was removed in TLC to give the final product which was then eluted from TLC with DCM/MeOH=10:1. The final product was further purified by prep. with the following conditions: Column XBridge Shield RP18 OBD 19*250 mm, 10 um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 22% B to 23% B for 15 min; UV 210/254 nm; Rt: 16.03 min. This resulted in 130 mg (34%) of Example 252 as a white solid. MS-ESI: 455 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.80 (1, s, 2H), 6.98 (s, 1H), 5.86 (s, 1H), 3 .24-3.17 (m, 1H), 2.84-2.80 (m, 2H), 2.77-2.66 (m, 2H), 2.09 (s, 3H), 1.98 -1.90 (m, 2H), 1.48 (s, 3H), 1.47 (s, 3H), 1.15 (d, J = 6.7 Hz, 6H). Table 34. The examples in the following table were prepared using conditions similar to those described in Example 252 and Scheme V from appropriate starting materials.

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ 2-(2-hydroxypropan-2-yl)-N'-((2,4,5,6-tetra- NH hydro- 1H-

N 253 672 N cyclobuta[b]cyclo-408

Y N

HO SO penta[e]pyridin-7-H 2N Oyl)carbamoyl)thiazol-5-sulfonimidamide N'-((3-(fluoromethyl)-O 1,2,3,5,6,7-hexa-NH 2 SOF hydrodicyclopen-NN ta[b,e]pyridin-8- 254 702 S HN N 454 yl)carbamoyl)-2-(2-hydroxypropan-2-OH yl)thiazol-5-sulfonimidamide N'-((1,2, 3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8- 255 692 HN N-yl)carbamoyl)-5-(2-435 N hydroxypropan-2-yl)-4-

S S O OH O methylthiophene-2-H2N sulfonimidamide N'-((2-cyclopropyl-3,7-dimethyl-6,7-dihydro-

HO 5H-cyclopenta-

H 256 656 N [b]pyridin-4-yl)carba-449

N N S moyl)-4-(2-hydroxy-

SOO propan-2-yl)thiophene-2-H2N sulfonimidamide 4-(2-hydroxypropan-2-yl)-N'-((2-isopropyl-3-HO methyl-6,7-dihydro-5H-257 681 HN N 437 N cyclopenta[b]pyridin-4-SSO yl)carbamoyl)thiophene-O 2-sulfonimidamide H2N

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ 1-(Difluoromethyl)-N'-F ((3-ethyl-1,2,3,5,6,7-NH hexa -hydrodicyclo-

F N 258 668 N N N penta[b,e]pyridin-8-425

S O yl)carbamoyl)-1H-H 2 N O pyrazol-3-sulfonimidamide N'-((2-cyclobutyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-

HO 259 658 HN N yl)carbamoyl)-4-(2-449 N hydroxypropan-2- S S O yl)thiophene-2-

H2N sulfonimidamide N'-((2-cyclopropyl-3-HO isopropyl-6,7-dihydro-5H-cyclopenta-260 667 HN N [b]pyridin-4-yl)carba-463 N moyl)-4 -(2-hydroxy-SSO propan-2-yl)thiophene-2-

H2N sulfonimidamide Acid 8-(3-(amino(2-O(2-hydroxypropan-2-NH2)

S O yl)thiazol-5-yl)(oxo)-λ6-

N N

S NH N (sulfanoylidene)urei- 261 703 466 do)-1,2,3,5,6,7-hexa-

OH HO hydrodicyclopen-

Ta[b,e]pyridine-3-carboxylic 1-Isopropyl-N'-((2-isopropyl-3-methyl-6,7-H 2 N O O dihydro-5H-

S 262 664 N N N cyclopenta[b]pyridin-4- 405 N N yl)carbamoyl)-1H-

H pyrazol-3-sulfonimidamide

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ 3-Fluoro-5-(2-F hydroxypropan-2-yl)-

F F N'-((3-methyl-2-F (trifluoromethyl)-6,7-di- 263 632 HN N 481

N hydro-5H- S S O cyclopenta[b]pyridin-4-

OH O H2N yl)carbamoyl)thiophene-2-sulfonimidamide F 4-(2-hydroxypropan-2-

F yl)-N'-((3-methyl-2-OH F (trifluoromethyl)-6,7-di- 264 624 HN N hydro-5H-463 N cyclopenta[b]pyridin-4-SSOyl)carbamoyl) thiophene-H 2 N O 2-sulfonimidamide N'-((3-cyclopropyl-2-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-

F 265 631 HN N yl)carbamoyl)-3-fluoro-467 N 5-(2-hydroxypropan-2-

SSO OH Oyl)thiophene-2-H2N sulfonimidamide N'-((3-cyclopropyl-2-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4- 266 630 N HN N yl)carbamoyl )-2-(2-450 N hydroxypropan-2-

S S O OH O yl)thiazol-5-H 2 N sulfonimidamide N'-((3-cyclopropyl-2-methyl-6,7-dihydro-5H-

OH cyclopenta[b]pyridin-4- 267 623 HN N yl)carbamoyl)-4-(2- 435 N hydroxypropan-2- S S O yl) thiophene-2- O sulfonimidamide H2N

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ 1-(Difluoromethyl)-N'- FF ((3-methyl-2-

F (trifluoromethyl)-6,7-dihydro-5H- 268 621 F HN N 439

N N cyclopenta[b]pyridin-4-

FNSO yl)carbamoyl)-1H-H2N Pyrazol-3-sulfonimidamide N'-((3-cyclopropyl-2-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4- 269 629 F HN N yl)carbamoyl)-1- NN (difluoromethyl)-1H-FNSO pyrazol-3-

H 2 N sulfonimidamide N'-((3-ethyl-2-CF3 (trifluoromethyl)-6,7-dihydro-5H- N HN N cyclopenta[b]pyridin-4- 270 610 478 N yl)carbamoyl)- 2-(2- SSO hydroxypropan-2-

OH O H2 Nyl)thiazol-5-sulfonimidamide N'-((3-ethyl-2-CF3(trifluoromethyl)-6,7-dihydro-5H-

F HN N cyclopenta[b]pyridin-4- 271 611 495 N yl)carbamoyl)-3-fluoro- S S O 5-(2-hydroxypropan-2-

OH O H2N yl)thiophene-2-sulfonimidamide N'-((3-ethyl-2-(trifluoromethyl)-6,7-dihydro-5H-H2N HNN CF3 cyclopenta[b]pyridin-4- 272 609 S 477 OON yl)carbamoyl)-4-(2-

HO S hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ N'-((3,7-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b] ]pyridin-4-273 608 478 yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide 4-Fluoro-5-(2-F hydroxypropan-2-yl)-(R)N '-(((R)-3-methyl-H 1,2,3,5,6,7-hexa-274 616 HO N 453

SNSN hydrodicyclopen-H2N OO ta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide 1-ethyl-N'-((1',5',6',7'-tetrahydro-2 'H- spiro[cyclopropane-

N H 1,3'-

N N N 275 604 dicyclopen- 401

SO NH2 ON ta[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7- hexa-NH hydrodicyclopen-

N 276 603 N N N ta[b,e]pyridin-8-403 S (yl)carbamoyl)-1-ethyl-H2N O O 1H-pyrazol-3-sulfonimidamide

Number- Mass Target Example Structure Exact IUPAC Name at End [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopent-NO ta[ b,e]pyridin-8-

H 277 304 N N yl)carbamoyl)-6,7-di-431

N N hydro-5H-

SOO Pyrazolo[5,1-H2N b][1,3]oxazine-3-sulfonimidamide N'-((2-cyclopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4 -

N H yl)carbamoyl)-6,7-di- 278 306 N N 417 N N hydro-5H-S pyrazolo[5,1-

O H2N O b][1,3]oxazine-3-sulfonimidamide N'-((1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridin-5-279,677yl) carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((3-methyl-2-(trifluoromethyl)-6,7 -di- 280 661 hydro-5H- 464 cyclopenta[b]pyridin-4-yl)carbamoyl)thiazol-5-sulfonimidamide N'-((2-(difluoromethyl)-3-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-281 647 446 yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Example 282 (Compound 619) N'-((2-(hydroxymethyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan -2-yl)thiazol-5-sulfonimidamide (Scheme VI) Step 1: 4-(3-(((tert-butyldimethylsilyl)amino)(2-(2-hydroxypropan-2-yl)thiazol-5-yl)( sodium oxo)-λ6-sulfaneylidene)ureido)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate

[002615] To a stirred solution of N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (270 mg, 0.76 mmol) in THF (20 ml) in a flask 50 ml round bottom layer under nitrogen, NaH (60% by weight, mineral oil dispersion, 91.2 mg, 2.28 mmol) was added at 0 °C. The resulting solution was stirred for 5 min at RT. To the above solution, ethyl 3-methyl-4-(((2,2,2-trichloroethoxy)carbonyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate ( 300 mg, 0.76 mmol) in THF (5 ml) by drip at 0 °C. The resulting solution was stirred overnight at RT. Then, the resulting solution was quenched by adding 2 ml of water. The resulting mixture was stirred for 1 h at RT. The resulting solution was concentrated in vacuo. This resulted in 440 mg of the title compound (crude product) as a white solid which was used in the next step without further purification. MS-ESI: 576 (M+1). Step 2: 4-(3-(Amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfanoylidene)ureido)-3-methyl-6,7-di- hydro-5H-cyclopenta[b]pyridine-2-carboxylic acid

[002616] To a stirred solution of 4-(3-(((tert-butyldimethylsilyl)amino)(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfanoylidene)ureido) Sodium -3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate (440 mg, crude product) in dioxane (10 ml) in a 50 ml round bottom flask was Concentrated HCl (2 ml) is added dropwise at 0°C. The resulting solution was stirred for 30 min at RT. The resulting solution was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 174 mg (52%, over two steps) of the title compound as an off-white solid. MS-ESI: 440 (M+1). Step 3: N'-((2-(hydroxymethyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2- yl)thiazol-5-sulfonimidamide

[002617] To a stirred solution of 4-(3-(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)ureido)-3-methyl-6 ,7-Dihydro-5H-cyclopenta[b]pyridine-2-carboxylic acid (150 mg, 0.34 mmol) in THF (10 mL) in a 50 mL round bottom flask under nitrogen was added BH3/ THF (1M, 1.0ml, 1.0mmol) dripped at 0°C. The resulting solution was stirred overnight at RT. The solution was quenched with MeOH (5 ml) and concentrated in vacuo. The crude product was purified by prep HPLC. with the following condition: XBridge Prep OBD C18 column, 30×150 mm, 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 5% B to 17% B du-

7 min; UV 254/210 nm; Rt: 6.63. This resulted in 100 mg (71%) of Example 282 as a white solid. MS-ESI: 426 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 7.82 (s, 1H), 4.48 (s, 2H), 2.84-2.81 (m, 2H), 2.71-2.69 ( m, 2H), 2.07 (s, 3H), 1.96-1.93 (m, 2H), 1.49 (s, 6H). Example 283 (Compound 618)

N HN No No OH S

SOH 2N O N'-((3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl) thiazol-2-sulfonimidamide (Scheme VII) Step 1: 5-(2-Hydroxypropan-2-yl)thiazol-2-sulfonimidamide

[002618] To a stirred solution of N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide (1.0 g, 2.98 mmol) in THF (10 ml) to a 100 ml round bottom flask was added HF/pyridine (70 wt%, 255 mg, 8.94 mmol) dropwise at 0 °C. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (20:1). This resulted in 630 mg (95.5%) of the title compound as an off-white solid. MS-ESI: 222(M+1). Step 2: N'-((3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl) thiazol-2-sulfonimidamide

[002619] To a stirred solution of 5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide (500 mg, 2.26 mmol) in THF (20 ml) in a 100 ml round bottom flask was added DBU (687 mg, 4.52 mmol) at RT. Then, 2,2,2-Trichloroethyl (3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (818 mg, 2.26 mmol) in THF (5 ml) was added to the stirred solution at RT. The resulting solution was stirred overnight at RT, quenched by the addition of water (2.0 ml) and concentrated in vacuo. The crude product was purified by prep HPLC. using the following conditions: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 um; mobile phase, water (10 mM NH4HCO3+0.1% NH3.H2O) and ACN (10% to 22% for 7 min); 254/210 nm; Rt: 5.88 min. This resulted in 310 mg (32%) of Example 283 as an off-white solid. MS-ESI: 436(M+1). 1H NMR (400 MHz, MeOH-d4) δ 7.68 (s, 1H), 2.89-2.86 (m, 4H), 2.54 (s, 3H), 2.08-1.99 ( m, 2H), 1.62 (s, 6H), 1.62-1.50 (m, 1H) 1.02-1.00 (m, 2H), 0.42-0.40 (m, 2H ). Table 35. The examples in the following table were prepared using conditions similar to those described in Example 283 and Scheme VII from appropriate starting materials. Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((2-cyclopropyl-3-methyl-6,7-dihydro-5H-HO cyclopenta[b]pyridin- 284 626 N HN N 436

N 4-yl)carbamoyl)-4-(2- S S O hydroxypropan-2-Oyl)thiazol-2-H 2 N sulfonimidamide

Table 36. The examples in the following table were prepared using conditions similar to those described in Example 28 and Scheme 2A from appropriate starting materials. Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N-((6-cyano-2,4-di-

HO isopropylpyridin-3-

N CN yl)carbamoyl)-4- 285 696 S (hydroxymethyl)-2-(2-481

N O HN hydroxypropan-2-

S HO HN N yl)thiazol-5-

N'-((3,3-dimethyl-

OH H 2N 1,2,3,5,6,7-hexa-

OSO hydrodicyclopent-Nta[b,e]pyridin-8- 286 682 447 NN HN N yl)carbamoyl)-4-(hydroxymethyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide N'-((3,3) -dimethyl-1,2,3,5,6,7-hexa-OH hydrodicyclopent-

N N S ta[b,e]pyridin-8- 287 653 N NH 2 O 447 N yl)carbamoyl)-3-

No

OH (hydroxymethyl)-1-isopropyl-1H-pyrazol-4-sulfonimidamide 2-(2-hydroxypropan-2-yl)-N'-((3-methyl-2-(1-methylcyclopropyl)-

N 6,7-dihydro-5H- 288 641 HO NH 2 O N 450

S S cyclopenta[b]pyridin- N N 4-

H yl)carbamoyl)thiazol-5-sulfonimidamide

Table 37. The examples in the following table were prepared using conditions similar to those described in Example 9 and Scheme 2 from appropriate starting materials. Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ 4-Chloro-N'- ((1,2,3,5,6,7-hexa- H2N O O hydrodicyclopen-

S N 289 694 N N ta[b,e]pyridin-8- 423/425 N N yl)carbamoyl)-1-

HCl isopropyl-1H-pyrazol-3-sulfonimidamide N'-((1,2,3,5,6,7-hexa-O NH 2 O hydrodicyclopent-Sta[b,e]pyridin-8- 290 687 NNN 403 NN yl)carbamoyl)-1-

H isopropyl-4-methyl-1H-pyrazol-3-sulfonimidamide 1-Isopropyl-N'-((3-methyl-1,2,3,5,6,7-H 2 NOO hexa-S hydrodicyclopen- 291 660 NN 403 N ta[b,e]pyridin-8-NNHyl)carbamoyl)-1H-imidazol-4-sulfonimidamide 5-(2-hydroxypropan-

NH 2 (R) 2-yl)-N'-(((R)-3-methyl-

N S O 1,2,3,5,6,7-hexa-

N 292 140c S N hydrodicyclopen- 436

HN ta[b,e]pyridin-8-yl)carbamoyl)thiazol-

HO 2-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ 2-(2-hydroxypropan-

NH2 O 2-yl)-N'-((3-methoxy-

ONLY

N 1,2,3,5,6,7-hexa-

N 293 635 S HN N hydrodicyclopent-452 ta[b,e]pyridin-8-OH yl)carbamoyl)thiazol-5-sulfonimidamide N'-((1,2,3,5,6,7-hexa-H 2 N O hydrodicyclopen-

OH S S O ta[b,e]pyridin-8-

N 294 689 HN N yl)carbamoyl)-2-(2-466

N hydroxypropan-2-yl)-O 4-(methoxymethyl)thiazol-5-sulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-H 2 N O hydrodicyclopen-

S S O

HO N ta[b,e]pyridin-8- 295 642 N HN N yl)carbamoyl)-4-480 (hydroxymethyl)-5-(2-OH hydroxypropan-2-yl)thiazol-2-sulfonimidamide N'-( (3,3-dimethyl-H 2 N 1,2,3,5,6,7-hexa-

ONSO hydrodicyclopent-Nta[b,e]pyridin-8- 296 686 S HN N 450 yl)carbamoyl)-5-(2-hydroxypropan-2-HO yl)thiazol-2-sulfonimidamide N'-((3,3) -dimethyl-

OH H 2 N 1,2,3,5,6,7-hexa-

O S O hydrodicyclopent- Nta[b,e]pyridin-8- 297 680 N N 464 S HN yl)carbamoyl)-4-(hydroxymethyl)-2-isopropylthiazol-5-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ 3-Cyano-N'-((3,3-dimethyl-1,2,3,5,6,7-H2 N N O hexa-

ONLY

N hydrodicyclopen- 298 674 HN N ta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-

OH yl)benzenesulfonimidamidide N'-((3,3-dimethyl-H 2 N O 1,2,3,5,6,7-hexa-SO hydrodicyclopen-

N N ta[b,e]pyridin-8- 299 684 HN 444 N yl)carbamoyl)-5-(2-hydroxypropan-2-yl)pyridine-3-

OH sulfonimidamide 5-(2-Hydroxypropan-2-yl)-N'-((1',5',6',7'-H 2 N O tetrahydro-2'H-

N S O

N spiro[cyclopropane-300 683 S HN N 1,3'- 448 dicyclopen-HO ta[b,e]pyridin]-8'-yl)carbamoyl)thiazol-2-sulfonimidamide N'-((2-cyclopropyl-3 - methyl-6,7-dihydro-H2N O 5H-

ONLY

HO S cyclopenta[b]pyridin-

N 301 679 HN N 4-yl)carbamoyl)-4-466

N (hydroxymethyl)-2-(2-

OH hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((3,3-dimethyl-

O O H2 N 1,2,3,5,6,7-hexa-

SN NH hydrodicyclopenta[b,e]pyridin-8-302 673 444 yl)carbamoyl)-6-(2-N hydroxypropan-2-Nyl)pyridine-3-HO sulfonimidamide H 2N N'-((3, 3-dimethyl-

OSO 1,2,3,5,6,7-hexa-N hydrodicyclopen-HO NN NH ta[b,e]pyridin-8-yl)carbamoyl)-1-(4-fluorophenyl)-5-( 2-hydroxypropan-2-yl)-N 1H-pyrazol-3-Fsulfonimidamide 5-(2-Hydroxypropan-H 2 N O 2-yl)-N'-((3-methyl-

S O 1,2,3,5,6,7-hexa-

HO NN hydrodicyclopent-304 664 NN HN 495 ta[b,e]pyridin-8-yl)carbamoyl)-1-phenyl-1H-pyrazol-3-sulfonimidamide N'-((3,3-dimethyl-H2N 1,2 ,3,5,6,7-hexa-

O S O hydrodicyclopent- N ta[b,e]pyridin-8-

HO N 305 663 N N HN 509 yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((2-cyclopropyl-3-H2N methyl-6,7-dihydro-

OSO 5H-HO N cyclopenta[b]pyridin-306 651 NN HN N 495 4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-sulfonimidamide H2N N' -((3,3-dimethyl-O 1,2,3,5,6,7-hexa-

S O N hydrodicyclopen- 307 659 N N ta[b,e]pyridin-8-451

HN N yl)carbamoyl)-1-phenyl-1H-pyrazol-3-sulfonimidamide N'-((3-ethyl-1,2,3,5,6,7-hexahydrodicyclopent-N ta[b,e] pyridin-8- 308 662 N 450 HO NH 2 O yl)carbamoyl)-2-(2-

Y Y N N hydroxypropan-2-

OH yl)thiazol-5-sulfonimidamide N'-((2-cyclobutyl-3-methyl-6,7-dihydro-5H-N-cyclopenta[b]pyridin-309 649 NH2 ON 450 HO 4-yl)carbamoyl) -2-(2-

Y Y N N hydroxypropan-2-

H yl)thiazol-5-sulfonimidamide 2-(2-Hydroxypropan-H 2 N O 2-yl)-N'-((2-isopropyl-

N S 3-methyl-6,7-dihydro- N O HN 5H- 310 650 S 438 N cyclopenta[b]pyridin-4-HO yl)carbamoyl)thiazol-5-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((3,3-dimethyl-OH 1,2,3,5,6,7-hexa- O hydrodicyclopent- NH2H SN ta [b,e]pyridin-8-311 648 NN yl)carbamoyl)-4-494

N S (hydroxymethyl)-2-(2-

Methoxypropan-2-

Oyl)thiazol-5-sulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-H 2 N O

The hydrodicyclopen-

N S ta[b,e]pyridin-8-

N N 312 615 N yl)carbamoyl)-5-(2-475

N H hydroxypropan-2-yl)-1-isopropyl-1H-

HO pyrazol-3-sulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-313 620 444 yl)carbamoyl) -4-(2-hydroxypropan-2-yl)pyridin-2-sulfonimidamide N'-((4-cyclopropyl-6-

The NH2 methylpyrimidin-2-

SSO HO NN yl)carbamoyl)-5-(2-314 185 N 397 HN hydroxypropan-2-Nyl)thiazol-2-sulfonimidamide 3-Bromo-N'-((1,2,3,5,6,7 -hexa-hydrodicyclopen- Br

HN N ta[b,e]pyridin-8- 315 690 499 N yl)carbamoyl)-5-(2-

HO S S O hydroxypropan-2-NH2 O yl)thiophene-2-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((2-cyclopropyl-3-OH ethyl-6,7-dihydro-5H-H2N N cyclopenta[b]pyridin- 316 675 NSN 4-yl)carbamoyl)-2-(2-450 SON hydroxypropan-2-HO yl)thiazol-5-sulfonimidamide 4-Fluoro-N'-((1,2,3,5,6,7- hexahydrodicyclopen-

F HN N ta[b,e]pyridin-8- 317 678 439 N yl)carbamoyl)-5-(2- S S O hydroxypropan-2-

OH O H2 Nyl)thiophene-2-sulfonimidamide N'-((3-ethyl-1,2,3,5,6,7-hexahydrodicyclopent-

F ta[b,e]pyridin-8-318 671 HN N (yl)carbamoyl)-3-467

No

S fluoro-5-(2-

OH SOO hydroxypropan-2-H 2 Nyl)thiophene-2-sulfonimidamide N'-((2-(tert-butyl)-3-methyl-6,7-dihydro-5H-HO cyclopenta[b]pyridin-319 657 HN N 451 N 4-yl)carbamoyl)-4-(2-SSO hydroxypropan-2-Oyl)thiophene-2-H 2 N sulfonimidamide N'-((2,3-dicyclopropyl-6,7-dihydro- 5H-

HO H cyclopenta[b]pyridin-320 670 N 461 N N 4-yl)carbamoyl)-4-(2-

S S O hydroxypropan-2-H2N O yl)thiophene-2-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ N'-((2-(cyclopropylmethyl)-3-methyl-6,7-dihydro-HO 5H- 321 655 HN N cyclopenta[ b]pyridin-449

N S 4-yl)carbamoyl)-4-(2-

SO H2N O hydroxypropan-2-yl)thiophene-2-sulfonimidamide N'-((3-cyclopropyl-2-ethyl-6,7-dihydro-5H-HO cyclopenta[b]pyridin-322 654 HN N 4- yl)carbamoyl)-4-(2-449 N hydroxypropan-2-SSO yl)thiophene-2-H 2 NO sulfonimidamide 1-Ethyl-N'-(((R)-3-methyl-1,2,3,5 ,6,7-hexahydrodicyclopen-323,634,389 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-Methyl-N'-(((R)-3-methyl (R) N'-(( (R)-3-methyl-1,2,3,5,6,7-hexa-N-hydrodicyclopent-

N 325 646a ta[b,e]pyridin-8-437

N HN yl)carbamoyl)-1-phenyl-N 1H-pyrazol-3-H2N S O sulfonimidamide

THE

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ 1-(Difluoromethyl)-N'- ((1',5',6',7'-tetrahydro-2'H-F spi-

Fro[cyclopropane- 326 638 N HN N 1,3'- 423 N N dicyclopen- S O ta[b,e]pyridin]-8'-

H 2N yl)carbamoyl)-1H-pyrazol-4-sulfonimidamide 1-(Difluoromethyl)-N'-

F ((3,3-dimethyl-F 1,2,3,5,6,7-hexa- N HN N hydrodicyclopen- 327 637 425 NN ta[b,e]pyridin-8-SOyl)carbamoyl)-1H - Pyrazol-4-H 2N sulfonimidamide N'-((1,2,3,5,6,7-OH hexahydrodicyclopen-H ta[b,e]pyridin-8- 328 633 N 415

No

N yl)carbamoyl)-4-(2-S hydroxypropan-2-H 2 N O O yl)benzenesulfonimidamide N'-((1,2,3,5,6,7-hexa-

OH hydrodicyclopen-HN N ta[b,e]pyridin-8- 329 625 415 yl)carbamoyl)-3-(2-

N-hydroxypropan-2-

S O O yl)benzenesulfonym H2 N idamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ 4-(2-hydroxypropan-OH 2-yl)-N'-((3-isopropyl-2-methyl-6,7-di- hydro- 330 622 HN N 5H-cyclopenta-437 N [b]pyridin-4-yl)carba-SSO moyl)thiophene-2-H 2 N O sulfonimidamide 1-Isopropyl-N'-((3-CF3 methyl-2-( trifluoromethyl)-6,7-dihydro-HN N 5H-cyclopenta- 331 628 431 NN [b]pyridin-4-NSOyl)carbamoyl)-1H-

H2N pyrazol-3-sulfonimidamide 1-(Difluoromethyl)-N'-F CF3 ((3-methyl-2-F(trifluoromethyl)-6,7-N HN N dihydro-5H- 332 617 439 NN cyclopenta[ b]pyridin-SO 4-yl)carbamoyl)-1H-

The H2N pyrazol-4-sulfonimidamide 4-Fluoro-5-(2-hydroxypropan-2-yl)-

F N'-((1',5',6',7'-tetrahydro-2'H-

HN 333 614 N spiro[cycloprop-465

N OH S S no-1,3'-dicyclo-

O H2N O penta[b,e]pyridin]-8'-yl)carbamoyl)thiophene-2-sulfonimidamide N'-((3,3-dimethyl-F 1,2,3,5,6,7-hexa- hydrodicyclopen-H ta[b,e]pyridin-8-

N 334 613 HO S N yl)carbamoyl)-4-467

No

S H2N O O fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Exemplary Target Mass Number Structure Exact IUPAC Name at End [M+H]+ 3-Fluoro-5-(2-F3C hydroxypropan-2-yl)-N'-((2-(2,2,2-F) trifluoroethyl)-6,7-di-335 602 HN N 481

N hydro-5H-cyclo- S S O penta[b]pyridin-4-

OH O yl)carbamoyl)thiophene-H 2 N 2-sulfonimidamide 5-((Dimethylamino)methyl)-3-F fluoro-N'-(((R)-3-H 2N(R)SOH methyl-1, 2,3,5,6,7- 336 636c N hexahydrodicyl-452

Y N

N N clopenta[b,e]pyridin-

8-yl)carbamoyl)-thiophene-2-sulfonimidamide 2-(2-Hydroxypropan-N 2-yl)-N'-((2-isopropyl-HO H 6,7-dihydro-5H-

N N

SSN 337 601 cyclopenta[b]pyridin-424 H2N OO 3-yl)carbamoyl)-thiazol-5-sulfonimidamide N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b] ,e]pyridin-8-338 685 429 yl)carbamoyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-sulfonimidamide

[002620] Table 38. The examples in the following table were obtained from chiral HPLC resolutions of racemic and diastereomeric mixture examples described above. The chiral column and eluents are listed in the table. As a convention, the fastest-eluting enantiomer is always listed first in the table, followed by the slower-eluting enantiomer of the pair. The symbol * in a chiral center denotes that the chiral center has been separated, and the absolute stereochemistry at that chiral center has not been determined.

The stereochemistry assigned in compound names is provisional.

Number- Eluent- LC-MS Ex. no. Target Structure Name IUPAC Column tes [M+H]+ Final (R) or (S)-N'- 20% of ((1,2,3,5,6, 7-hexa-CHI-EtOH H 2N hydrodicyclopen-RAL-OO in * SN ta[b,e]pyridin-8-PAK IG, 339 685b F3C NN MTBE 429 NN yl)carbamoyl)-1- 20*250 H (NH3 -(2,2,2-trifluoroethyl)-mm, 5 MeOH 1H-pyrazol-3- a 10 mM)sulfonimidamide (S) or (R)-N'- 20% of ((1,2,3,5, 6,7-hexa-CHI-EtOH hydrodicyclopen-RAL-H2N OO in * SN ta[b,e]pyridin-8-PAK IG, 340 685a F 3C NN MTBE 429 NN yl)carbamoyl)-1- 20*250 H (NH3-(2,2,2-trifluoroethyl)-mm, 5 MeOH 1H-pyrazol-3- a 10 mM)sulfonimidamide (R) or (S)-4-Chloro-N'-((1,2,3 ,5,6,7-CHI- 50% hexa-H 2 N OO RAL- EtOH S * hydrodicyclopen- NN PAK IE, in Hex 341 694b N ta[b,e]pyridin-8- 423/425 NN 2*25 ( NH 3 .Me (H yl)carbamoyl)-1- Cl cm, 5 OH 8 isopropyl-1H- one mM) pyrazol-3-sulfonimidamide (S) or (R)-4-Chloro-N'-((1,2, 3,5,6,7- CHI- 50% hexa-H 2 N O RAL- EtOH O hydrodicyclopen- S * PAK IE, in Hex 342 694a NNN ta[b,e]pyridin-8- 423/425 NN 2*25 (NH3 .Me (H yl)carbamoyl)-1- Cl cm, 5 OH 8 isopropyl-1H- one mM) pyrazol-3-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (R) or (S)-N'- ((1,2,3,5,6,7-hex - CHI- 50% H2N OO hydrodicyclopen-RAL-EtOH Sta[b,e]pyridin-8-PAK IG, in Hex 343 687b N * NN 403 NN yl)carbamoyl)-1- 2*25 (NH3.Me

H isopropyl-4-methyl-cm, 5OH 8 1H-pyrazol-3-one mM)sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexa-CHI - 50% H2N OO hydrodicyclopen-RAL-EtOH Sta[b,e]pyridin-8-PAK IG, in Hex 344 687a N * NN 403 NN yl)carbamoyl)-1-2*25 (NH3.Me

H isopropyl-4-methyl-cm, 5OH 8 1H-pyrazol-3-one mM)sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa-CHI - 30% H2 NO hydrodicyclopen- * O RAL- EtOH HO S ta[b,e]pyridin-8-

s

N N PAK IG, in Hex 345 689b N yl)carbamoyl)-2-(2-466 N H 2*25 (NH3.Me hydroxypropan-2-yl)-

0 cm, 5 OH 8 4-one mM) (methoxymethyl)thiazol-5-sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexa-CHI-30% of H2N O hydrodicyclopen- * O RAL- EtOH HO S ta[b,e]pyridin-8-

s

N N PAK IG, in Hex 346 689a N yl)carbamoyl)-2-(2-466 N H 2*25 (NH3.Me hydroxypropan-2-yl)-

0 cm, 5 OH 8 4- mM) (methoxymethyl)thiazol-5-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7- hexa-CHI-H2N

30% S*SO hydrodicyclopen-RAL-HO IPA in N ta[b,e]pyridin-8-PAK IC, 347 642b N HN N Hex 480 yl)carbamoyl)-4-2*25 (0.1% OH (hydroxymethyl)-5-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiazol-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((3,3-dimethyl-1,2,3,5 ,6,7- hexa-CHI-H2N

30% S*SO hydrodicyclopen-RAL-HO IPA in N ta[b,e]pyridin-8-PAK IC, 348 642a N HN N Hex 480 yl)carbamoyl)-4-2*25 (0.1% OH (hydroxymethyl)-5-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiazol-2-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2 ,3,5,6,7- H 2N CHI- * The hexa- 30% of NSO RAL-

N-hydrodicyclopen-MeOH:

S PAK ID, 349 686b HN ta[b,e]pyridin-8-ACN=4: 450 N 2*25 yl)carbamoyl)-5-(2-1 in HO cm, 5 hydroxypropan-2-CO 2 one yl) thiazol-2-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-H 2N CHI- * O hexa- 30% NSO RAL-

N-hydrodicyclopen-MeOH:

S PAK ID, 350 686a HN ta[b,e]pyridin-8-ACN=4: 450 N 2*25 yl)carbamoyl)-5-(2-1 in HO cm, 5 hydroxypropan-2-CO 2 one yl) thiazol-2-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-

CHIRAL hexa- 30% of

ART hydrodicyclopen-EtOH Cellulota[b,e]pyridin-8- in Hex 351 170b se-SB, 494 yl)carbamoyl)-2-(2-(NH 3 .Me 5 um, hydroxypropan-2-yl)-OH 8 250*20 4-mM) mm (methoxymethyl)thiazole-5-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-N'-((3,3-dimethyl-1,2,3,5) ,6,7-

CHIRAL OH 2N hexahydrodicyl- 30% of * O ART SO clopen- EtOH Cellulo- NN ta[b,e]pyridin-8- in Hex 352 170a S HN N se-SB, 494 yl)carbamoyl)-2-( 2-(NH3.Me 5um, hydroxypropan-2-yl)-OH 8 HO 250*20 4-(methoxymethyl-mM)mm)thiazol-5-sulfonimidamide (R) or (S)-N'-((3) ,3-dimethyl-1,2,3,5,6,7- 50% CHI-hexahydrodi-EtOH RAL-cyclopenta[b,e]-(0.1% PAK IC, 353 680b pyridin-8- yl)carba-de 464 2*25 moyl)-4-(hydroxy-NH 3 .H 2 cm, 5 methyl)-2-isopro-O) in a pilthiazol-5-Hex sulfonimidamide (S) or (R)-N' -((3,3-OH dimethyl-1,2,3,5,6,7-50% H 2 N CHI-hexahydrodi-EtOH

N * S O RAL- O cyclopenta[b,e]-(0.1% S N PAK IC, 354 680a pyridin-8-yl)card- 464 HN 2*25

N-bamoyl)-4-(hydro-NH3.H2 cm, 5-ximethyl)-2-isopro-O) in a pilthiazol-5-sulfo-Hexnimidamide (R) or (S)-N'-((3,3) - dimethyl-1,2,3,5,6,7-hexahydro-Chiral- 40% dicyclopenta[b,e]-pak AD, IPA 355 682b pyridin-8-yl)car-2*25 (NH 3 2,447 bamoyl)-4-(hydro-cm, 5 mM) in xymethyl)-1-isopro-one CO 2 pyl-1H-pyrazol-3-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((3,3-dimethyl-1,2,3,5 ,6,7- OH hexa- H 2N Chiral- 40% O hydrodicyclopen- * SO pak AD, IPA

N ta[b,e]pyridin-8- 356 682a N 2*25 (NH 3 2 447 yl)carbamoyl)-4-

NN HN cm, 5 mM) in (hydroxymethyl)-1- a CO 2 isopropyl-1H-pyrazol-3-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3, 5,6,7- CHI-hexa- 30% RAL-hydrodicyclopen-EtOH

PAK ta[b,e]pyridin-8-(NH 3 - 357 653b AD, 447 yl)carbamoyl)-3-MeOH 2 2*25 (hydroxymethyl)-1-mM) in cm, 5 isopropyl-1H-CO 2 a pyrazole -4-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7-CHI-hexa-30% RAL-OH hydrodicyclopen-EtOH

N N PAK S * ta[b,e]pyridin-8-(NH3- 358 653a N NH2 O AD, 447

NN yl)carbamoyl)-3-MeOH 2 2*25 OH (hydroxymethyl)-1-mM) in cm, 5 isopropyl-1H-CO 2 a pyrazol-4-sulfonimidamide (R) or (S)-3-Cyano-N '-((3,3-dimethyl-1,2,3,5,6,7-35% Chiral-hexa-MeOH pak IC, hydrodicyclopen-(NH3- 359 674b 2*25 468 ta[b,e] pyridin-8-MeOH 2 cm, 5 yl)carbamoyl)-5-(2-mM) in a hydroxypropan-2-CO 2 yl)benzenesulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-3-Cyano-N'-((3,3-H2N dimethyl-1, 2,3,5,6,7- 35% NO Chiral-SO hexa-MeOH * pak IC, N hydrodicyclopent- (NH 3 - 360 674a HN N 2*25 468 ta[b,e]pyridin-8-MeOH 2 cm, 5 yl)carbamoyl)-5-(2-mM) in OH a hydroxypropan-2-CO 2 yl)benzenesulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2, 3,5,6,7- CHIRAL hexa-ART hydrodicyclopenulo- 25% of 361 684b ta[b,e]pyridin-8-se-SB, EtOH 444 yl)carbamoyl)-5-(2-2*25 in Hex hydroxypropan-2-cm, 5yl)pyridine-3- a sulfonimidamide (R) or (S)-N'-H 2 N ((3,3-dimethyl-CHIRAL * O 1,2,3,5,6, 7-hex-ART

ONLY

N N hydrodicyclopen-Cellulo- 25% of 362 684a HN ta[b,e]pyridin-8-se-SB, EtOH 444

Nyl)carbamoyl)-5-(2-2*25 in Hex hydroxypropan-2-cm, 5

HO yl)pyridine-3- a sulfonimidamide (S) or (R)-5-(2-hydroxypropan-2-yl)-N'-((1',5',6',7'-tetra-CHIRAL 40 % hydro-2'H-ART IPA in spi-Cellulo-EtOH 363 683b ro[cyclopropanose-SB, 448 (0.1% 1,3'- 2*25 dicyclopentcm, 5 DEA) ta[ b,e]pyridin]-8'-an yl)carbamoyl)thiazol-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-5-(2-hydroxypropan-2-yl)-N'-((1) ',5',6',7'-tetra-CHIRAL 40% H2N O hydro-2'H-ART * SO IPA in N spi- Cellulo- N EtOH 364 683a HN N ro[cyclopropanose-SB, 448 S (0.1% 1,3'- 2*25 dicyclopen-cm, 5 HO DEA) ta[b,e]pyridin]-8'-an yl)carbamoyl)thiazol-2-sulfonimidamide (S) or ( R)-N'-((3,3-dimethyl-1,2,3,5,6,7-CHIRAL hexa-ART hydrodicyclopentin-Cellulo-30% of 365 673b ta[b,e]pyridin-8-se -SB, EtOH 444 yl)carbamoyl)-6-(2-2*25 in Hex hydroxypropan-2-cm, 5 yl)pyridine-3- a sulfonimidamide (R) or (S)-N'-((3, 3- OO dimethyl-1,2,3,5,6,7-CHIRAL H2N hexa-ART * SN NH hydrodicyclopent-Cellulo- 30% of 366 673a ta[b,e]pyridin-8-se-SB, EtOH 444 N yl)carbamoyl)-6-(2-2*25 in Hex N hydroxypropan-2-cm, 5 HO yl)pyridine-3- a sulfonimidamide (R) or (S)-N'-((3,3- Lux 5 dimethyl-1,2,3,5,6,7- a hexa-50% Cellulohydrodicyclopen-MeOH se-4, ta[b,e]pyridin-8-(NH3-367 705b AXIA 527yl) carbamoyl)-1-(4-MeOH 2 emba-fluorophenyl)-5-(2-mM) on the side, hydroxypropan-2-yl)-CO 2 2.12*25 1H-pyrazol-3-cmsulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (S) or (R)-N'-((3,3- OO Lux 5 H2N dimethyl-1,2 ,3,5,6,7- S a * N NH hexa- 50% Cellulohydrodicyclopen-MeOH N se-4, N ta[b,e]pyridin-8-(NH 3 - 368 705a AXIA 527 HO yl) carbamoyl)-1-(4-MeOH 2N emba-fluorophenyl)-5-(2-mM) on the side, hydroxypropan-2-yl)-CO 2 2.12*25 1H-pyrazol-3-F in sulfonimidamide (R ) or (S)-5-(2-hydroxypropan-2-yl)-CHI-N'-((3-methyl-30% RAL-1,2,3,5,6,7-hexa-EtOH PAK IC, 369 664b hydrodicyclopen- in Hex 495 2*25 ta[b,e]pyridin-8-(0.1% cm, 5 yl)carbamoyl)-1- from FA) a phenyl-1H-pyrazol-3-sulfonimidamide (S) or (R)-5-(2-hydroxypropan-2-yl)-CHI-H 2N O N'-((3-methyl-30% SORAL-HO *

N 1,2,3,5,6,7-hexa-EtOH PAK IC, 370 664a NN HN N hydrodicyclopen-em Hex 495 2*25 ta[b,e]pyridin-8-(0.1% cm, 5 yl)carbamoyl)-1- from FA) a phenyl-1H-pyrazol-3-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7) - H2N CHI- The hexa- 30% of *SO RAL-

N hydrodicyclopen-EtOH HO N PAK IC, 371 663b NN HN ta[b,e]pyridin-8- in Hex 509 2*25 yl)carbamoyl)-5-(2-(0.1% cm, 5 hydroxypropan-2 -yl)- from FA) a 1-phenyl-1H-pyrazol-3-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((3,3-dimethyl-1,2,3,5 ,6,7-CHI-hexa-30% RAL-hydrodicyclopen-EtOH PAK IC, 372,663a ta[b,e]pyridin-8- in Hex 509 2*25 yl)carbamoyl)-5-(2-(0 .1% cm, 5 hydroxypropan-2-yl)- of FA) a 1-phenyl-1H-pyrazol-3-sulfonimidamide (R) or (S)-N'-((2-cyclopropyl-3-methyl-CHI - 6,7-dihydro-5H- 30% RAL-cyclopen-EtOH PAK IG, 373 651b ta[b]pyridin-4- in Hex 495 20*250 yl)carbamoyl)-5-(2-(0) .1% mm, 5 hydroxypropan-2-yl)- of FA) a 1-phenyl-1H-pyrazol-3-sulfonimidamide (S) or (R)-N'-((2-cyclopropyl-3-methyl-CHI - H2N * O 6,7-dihydro-5H- 30% SO RAL-

HO N cyclopen-EtOH PAK IG, 374 651a NN HN N ta[b]pyridin-4- in Hex 495 20*250 yl)carbamoyl)-5-(2-(0.1% mm, 5 hydroxypropan-2-yl )- from FA) a 1-phenyl-1H-pyrazol-3-sulfonimidamide (R) or (S)-N'-((3,3-H 2 N dimethyl-1,2,3,5,6,7-CHI - * 30% SO hexa-RAL-EtOH N hydrodicyclopen-PAK IG, 375 659b NN in Hex 451 HN N ta[b,e]pyridin-8- 5*25 (0.1% yl)carbamoyl)-1 - cm, 5 of FA) phenyl-1H-pyrazol-3-a sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-CHI- 30% hexa-RAL-EtOH hydrodicyclopen-PAK IG, 376 659a in Hex 451 ta[b,e]pyridin-8-5*25 (0.1% yl)carbamoyl)-1-cm, 5 FA)phenyl -1H-pyrazole-3- a sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((2-cyclobutyl-3-methyl-CHIRAL 6,7- dihydro-5H-ART 30% cyclopen-Cellulo-EtOH

N 377 649b HO NH2 O N ta[b]pyridin-4-se-SB, in Hex 450 *

S S

N N yl)carbamoyl)-2-(2-2*25 (0.1%

OH hydroxypropan-2-cm, 5 of FA)yl)thiazol-5-a sulfonimidamide (R) or (S)-N'-((2-cyclobutyl-3-methyl-CHIRAL 6,7-dihydro-5H - ART 30% cyclopen-Cellulo-EtOH 378 649a ta[b]pyridin-4-se-SB, in Hex 450 yl)carbamoyl)-2-(2-2*25 (0.1% hydroxypropan-2-cm , 5 of FA)yl)thiazol-5-a sulfonimidamide (S) or (R)-2-(2-hydroxypropan-2-yl)-CHIRAL N'-((2-isopropyl-3-ART 30% methyl -6,7-dihydro-Cellulo-EtOH 650b N 379 HO * NH2 ON 5H-se-SB, in Hex 438

S S

The N N cyclopen-2*25 (0.1%

H ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiazol-a 5-sulfonimidamide (R) or (S)-2-(2-hydroxypropan-2-yl)-CHIRAL N'-( (2-isopropyl-3-ART 30% methyl-6,7-dihydro-Cellulo-EtOH 380 650a 5H-se-SB, in Hex 438 cyclopen-2*25 (0.1% ta[b]pyridin -4- cm, 5 of FA)yl)carbamoyl)thiazol-a 5-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((3,3-dimethyl-1,2,3,5 ,6,7-

CHIRAL OH hexa- 20%

ART NH2H hydrodicyclopen-EtOH S * Cellulo- N ta[b,e]pyridin-8- in Hex 381 648b N N se-SB, 494

NS ( S)-N'-((3,3-dimethyl-

CHIRAL 1,2,3,5,6,7-hexa- 20% of

ART hydrodicyclopen-EtOH Cellulota[b,e]pyridin-8- in Hex 382 648ase-SB, 494yl)carbamoyl)-4-(NH 3 .Me 2*25(hydroxymethyl)-2-(2-OH 8 cm, 5 methoxypropan-2-mM) an yl)thiazol-5-sulfonimidamide (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7-H 2 N hexa- CHI- * The 40% of

S Hydrodicyclopen- RAL- N IPA in

N N N ta[b,e]pyridin-8-PAK IC, 383 615b N Hex 475 H yl)carbamoyl)-5-(2-2*25 (0.1% hydroxypropan-2-yl)-cm, 5

HO from FA) 1-isopropyl-1H- a pyrazol-3-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-CHI - 40% hydrodicyclopen-RAL-IPA in ta[b,e]pyridin-8-PAK IC, 384 615a Hex 475 yl)carbamoyl)-5-(2-2*25 (0.1% hydroxypropan-2-yl) )- cm, 5 of FA) 1-isopropyl-1H- a pyrazol-3-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-N'-((3,3-dimethyl-1,2,3,5) ,6,7-hexa-Chiral- 30% hydrodicyclopenpak IC, EtOH 385 620b ta[b,e]pyridin-8-2*25 in Hex 444 yl)carbamoyl)-4-(2-cm, 5 ( 0.1% hydroxypropan-2-one of FA)yl)pyridine-2-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7- hexa-Chiral- 30% hydrodicyclopen-pak IC, EtOH 386 620a N HN N ta[b,e]pyridin-8-2*25 in Hex 444

Nyl)carbamoyl)-4-(2-cm, 5 (0.1% * SO

HO H 2N O hydroxypropan-2-um of FA) yl)pyridine-2-sulfonimidamide (R) or (S)-N'-((4-O-cyclopropyl-6-Chiral- 30% OH NH 2 S * SO methylpyrimidin -2- pak ID, EtOH

N N 387 185a N yl)carbamoyl)-5-(2-2*25 in Hex 397

HN

N-hydroxypropan-2-cm, 5 (0.1% yl)thiazol-2-um of FA)sulfonimidamide (S) or (R)-N'-((4-O-cyclopropyl-6-Chiral- 30% OH NH2 S * SO methylpyrimidin-2-pak ID, EtOH

N N 388 185b N yl)carbamoyl)-5-(2-2*25 in Hex 397

HN

N-hydroxypropan-2-cm, 5 (0.1% yl)thiazol-2-um of FA)sulfonimidamide (R) or (S)-N'-((2-fluoro-3,5-di-Chiral-20 % isopropylpyridin-4-pak IA, IPA in 389 115b yl)carbamoyl)-2-(2-2*25 Hex 444 hydroxypropan-2-cm, 5 (0.1% yl)thiazol-5-um of FA) sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (S) or (R)-N'-((2-F fluoro-3,5-di-Chiral- 20% isopropylpyridin-4-pak IA, IPA in

N HN N 390 115a yl)carbamoyl)-2-(2-2*25 Hex 444

N HO S hydroxypropan-2-cm, 5 (0.1%

s

O H2N *Oyl)thiazol-5-um of FA)sulfonimidamide (S) or (R)-4-Fluoro-N'-CHIRAL 30% ((1,2,3,5,6,7-hexa- ART EtOH hydrodicyclopen-Cellulo- in Hex 391 701b ta[b,e]pyridin-8-se-SB, 439 (NH 3 .Meyl)carbamoyl)-5-(2-2*25 OH 8 hydroxypropan-2-cm, (R) or (S)-4-Fluoro-N'-CHIRAL 30% ((1,2,3,5,6,7-hexa-ART EtOH)

HO F hydrodicyclopen-Cellulo- in Hex 392 701a HN N ta[b,e]pyridin-8-se-SB, 439 SN (NH 3 .Meyl)carbamoyl)-5-(2-2*25 SO OH 8 * O hydroxypropan-2-cm, 5 H 2 N mM)yl)thiophene-3- a sulfonimidamide (R) or (S)-N'- 20% ((1,2,3,5,6,7-hexa-CHI- EtOH hydrodicyclopen-RAL- in HN N ta[b,e]pyridin-8-PAK IG, 393 692b MTBE 435 N yl)carbamoyl)-5-(2-2*25

S S O (NH3-OH *

The hydroxypropan-2-yl)-cm, 5 MeOH H 2 N 4-methylthiophene-2- a 10 mM)sulfonimidamide (S) or (R)-N'- 20% of ((1,2,3,5,6 ,7-hexa-CHI-EtOH hydrodicyclopen-RAL- in ta[b,e]pyridin-8-PAK IG, 394,692a MTBE 435 yl)carbamoyl)-5-(2-2*25(NH3-hydroxypropan-2- yl)-cm, 5 MeOH 4-methylthiophene-2- a 10 mM) sulphonimide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (R) or (S)-N'- ((1,2,3,5,6,7-hex - CHI- 35% hydrodicyclopen-RAL-EtOH ta[b,e]pyridin-8-PAK IG, in Hex 395 695b 435 yl)carbamoyl)-5-(2-2*25 (NH 3 .Me hydroxypropan-2- yl)-cm, 5 OH 8 3-methylthiophene-2-one mM)sulfonimidamide (S) or (R)-N'-((1,2,3,5,6,7-hexa-CHI- 35% of hydrodicyclopen-RAL-EtOH HN N ta[b,e]pyridin-8-PAK IG, in Hex 396 695a 435 N yl)carbamoyl)-5-(2-2*25 (NH 3 .Me S * SO hydroxypropan-2- yl)-cm, 5 OH 8

OH O H2N 3-methylthiophene-2-one mM)sulfonimidamide (R) or (S)-3-chloro-N'-((1,2,3,5,6,7-CHI- 30% hexa-RAL - EtOH hydrodicyclopen-PAK IG, in Hex 397 691b ta[b,e]pyridin-8-455 2*25 (NH 3 .Meyl)carbamoyl)-5-(2-cm, 5 OH 8 hydroxypropan-2-one mM ) yl)thiophene-2-sulfonimidamide (S) or (R)-3-chloro-N'-((1,2,3,5,6,7-CHI- 30% hexa-RAL-EtOH hydrodicyclopen-Cl PAK IG, in Hex 398 691a HN N ta[b,e]pyridin-8- 455 N 22*25 (NH 3 .Meyl)carbamoyl)-5-(2-S * SO cm, 5 OH 8 OH O hydroxypropan- 2- H 2 N one mM) yl)thiophene-2-sulfonimidamide (S) or (R)-4-chloro-N'-((1,2,3,5,6,7-CHIRAL 40% hexa-ART EtOH Cl hydrodicyclopen-Cellulo-688b HN N in Hex 399 ta[b,e]pyridin-8-se-SB, 455 N (NH3.Me

S S O yl)carbamoyl)-5-(2-2*25 OH *

OH 8 hydroxypropan-2-cm, 5 H2N mM) yl)thiophene-2- a sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (R) or (S)-4-chloro-N'-((1,2,3,5,6) ,7-CHIRAL 40% hexa-ART EtOH hydrodicyclopen-Cellulo- in Hex 400 688a ta[b,e]pyridin-8-se-SB, 455 (NH 3 .Meyl)carbamoyl)-5-(2-2* 25 OH 8 hydroxypropan-2-cm, 5 mM) yl)thiophene-2- a sulfonimidamide (R) or (S)-3-Bromo-N'-CHI- 50% of ((1,2,3,5, 6,7-hexa-RAL-EtOH hydrodicyclopen-Br

HN N PAK IG, in Hex 401 690b ta[b,e]pyridin-8-499 HO N 2*25 (NH 3 .Me SS * O yl)carbamoyl)-5-(2-cm, 5 OH 8 H 2 N O hydroxypropan -2- one mM)yl)thiophene-2-sulfonimidamide (S) or (R)-3-Bromo-N'-CHI- 50% ((1,2,3,5,6,7-hexa-RAL - EtOH hydrodicyclopen-PAK IG, in Hex 402 690a ta[b,e]pyridin-8-499 2.0*25 (NH 3 .Meyl)carbamoyl)-5-(2-cm, 5OH 8 hydroxypropan-2- one mM) yl)thiophene-2-sulfonimidamide (S) or (R)-2-(2-hydroxypropan-2-yl)-CHIRAL

F F 30% N'-((3-methyl-2-ART F EtOH(trifluoromethyl)-6,7-Cellulo-

HN N in Hex 403 661b N dihydro-5H-se-SB, 464 N (NH3.Me

S cyclopen- 2*25 OH * S

OO OH 8 ta[b]pyridin-4-cm, 5 H 2 N mM) yl)carbamoyl)thiazol-a 5-sulfonimidamide (R) or (S)-2-(2-hydroxypropan-2-yl)-CHIRAL 30% of N'-((3-methyl-2-ART EtOH(trifluoromethyl)-6,7-Cellulo- in Hex 404 661a dihydro-5H-se-SB, 464 (NH3.Me cyclopen-2*25 OH 8 ta[b]pyridin-4-cm, 5mM)yl)carbamoyl)thiazol-a 5-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((2-(difluoromethyl)-3-

CHIRAL methyl-6,7-dihydro-

F ART

F 5H- Cellulo- 30% N cyclopen- 405 647b HN N se-SB, EtOH 446 N ta[b]pyridin-4-OH S * S 2*25 in CO2

O O yl)carbamoyl)-2-(2-H 2 N cm, 5-hydroxypropan-2-umyl)thiazol-5-sulfonimidamide (R) or (S)-N'-((2-(difluoromethyl)-3-

CHIRAL methyl-6,7-dihydro-

ART 5H- Cellulo-30% cyclopen- 406 647ase-SB, EtOH 446 ta[b]pyridin-4-2*25 in CO 2 yl)carbamoyl)-2-(2-cm, 5-hydroxypropan-2-umyl )thiazol-5-sulfonimidamide (R) or (S)-N'-((2-cyclopropyl-3-methyl-10% CHI-6,7-dihydro-5H-EtOH RAL-cyclopen- in PAK IG , 407 676b ta[b]pyridin-4-MTBE 411 20*250 yl)carbamoyl)-1-(NH 3 -mm, 5 (difluoromethyl)-1H-MeOH a pyrazol-3-10 mM)sulfonimidamide (S) or ( R)-N'-((2-cyclopropyl-3-methyl-10% CHI-6,7-dihydro-5H-EtOH F RAL-

H cyclopen- in N N PAK IG, 408 676a F N * N ta[b]pyridin-4-MTBE 411

YN 20*250

O O yl)carbamoyl)-1-(NH 3 -H 2 N mm, 5 (difluoromethyl)-1H-MeOH a pyrazol-3-10 mM) sulfonimamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-N'-((2-cyclopropyl-3-ethyl- 30% of 6, 7-dihydro-5H-H Chiral-IPA in ON cyclopen-H2N pak AD, Hex 409 181b N ta[b]pyridin-4-449 HO * SN 2*25 cm (NH 3 .M yl)carbamoyl)-4 -(two-

SO 5 an eOH 8 hydroxypropan-2-mM)yl)thiophene-2-sulfonimidamide (S) or (R)-N'-((2-cyclopropyl-3-ethyl-30% 6,7-dihydro- 5H-Chiral-IPA in cyclopenpak AD, Hex 410 181a ta[b]pyridin-4-449 2*25 cm (NH 3 .M yl)carbamoyl)-4-(2- 5 um eOH 8 hydroxypropan-2-mM ) yl)thiophene-2-sulfonimidamide (S) or (R)-N'-((2-cyclopropyl-3-ethyl-CHIRAL 25% 6,7-dihydro-5H-ART OH MeOH H 2 N N cyclopen- Cellulo-N * (NH3-411 675b SN ta[b]pyridin-4-se-SB, 450

SO MeOH 2N yl)carbamoyl)-2-(2-2*25 HO mM) in hydroxypropan-2-cm, 5 CO 2 yl)thiazol-5- a sulfonimidamide (R) or (S)-N'-(( 2-cyclopropyl-3-ethyl-CHIRAL 25% 6,7-dihydro-5H-ART MeOH Cyclopen-Cellulo-(NH 3 - 412 675a ta[b]pyridin-4-se-SB, 450 MeOH 2 yl) carbamoyl)-2-(2-2*25 mM) in hydroxypropan-2-cm, 5CO 2 yl)thiazol-5-a sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-4-(2-hydroxypropan-2-yl)- 10% N'- ((2-Isopropyl-3-EtOH Chiral-methyl-6,7-dihydro-in

HO pak IC, HN N 5H-Hex:DC 413 681b 2*25 437 N cyclopen-M (3:1,

S cm, 5 * SO ta[b]pyridin-4-NH 3 - O a H 2 N yl)carbamoyl)thiophene MeOH o-2- 10 mM)sulfonimidamide (S) or (R)-4-(2-hydroxypropan-2- yl)- 10% N'-((2-isopropyl-3-EtOH Chiral-methyl-6,7-dihydro- in pak IC, 5H-Hex:DC 414 681a 2*25 437 cyclopen-M (3 :1, cm. - N'-((3-methyl-2-(1-CHI-30% methylcyclopropyl)-RAL-EtOH 6,7-dihydro-5H-PAK IG, 415 669b in Hex 449 cyclopen-2*25 ( 0.1% ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiophene an o-2-sulfonimidamide (S) or (R)-4-(2-hydroxypropan-2-yl)-CHI - N'-((3-methyl-2-(1- 30% RAL-

HO methylcyclopropyl)-EtOH

HN N PAK IG, 416 669a 6,7-dihydro-5H- in Hex 449 N 2*25

S cyclopenta[b]pyri-(0.1% * S

The 0 cm, 5 din-4-yl)carbamoyl)- of FA) H2N is a thiophene-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final Lux 5 (R) or (S)-N'-((2- a 40% cyclopropyl-6,7 -di- Cellulo- EtOH

OH hydro-5H-cyclo-Nse-4 in H2N penta[b]pyridin-4- 417 176b HO * N AXIA MeOH 421 SN yl)carbamoyl)-4-(2-O emba-(NH3-S hydroxypropan-2 - side, MeOH 2 yl)thiophene-2- 2.12*25 mM) sulfonimidamide in (S) or (R)-N'-((2-Lux 5 cyclopropyl-6,7-di- a 40% hydro -5H- Cellulo-EtOH cyclopense-4 in 418 176a ta[b]pyridin-4-AXIA MeOH 421 yl)carbamoyl)-4-(2-emba-(NH 3 -hydroxypropan-2-sided, MeOH 2 yl) thiophene-2- 2.12*25 mM) sulfonimidamide in Lux 5 (R) or (S)-4-(2-a hydroxypropan-2-yl)-40% Cellulo-N'-((2-isopropyl- MeOH se-4 6,7-dihydro-5H-(NH3- 419 182b AXIA 423 cyclopenta[b]pi-MeOH 2 embaridin-4-yl)carba- mM) on the side, moyl)thiophene-2- CO2 2.12*25 sulfonimidamide in Lux 5 (S) or (R)-4-(2-a hydroxypropan-2-yl)-40% Cellulose

OH N'-((2-isopropyl-MeOH Nse-4 H2N 6,7-dihydro-5H-(NH 3 - 420 182a HO * N AXIA 423 SN cyclopenta[b]-MeOH 2 O emba- S pyridin- 4-yl)carbam-mM) on side, moyl)thiophene-2-CO 2 2.12*25 sulfonimidamide in (S) or (R)-4-Fluoro-N'-CHIRAL 30% of ((1,2, 3,5,6,7-hexa-ART

F EtOH hydrodicyclopen-Cellulo-HN N in Hex 421 678b ta[b,e]pyridin-8-se-SB, 439 N (NH3.Me

S S O yl)carbamoyl)-5-(2-2*25

OH O OH 8 * hydroxypropan-2-cm, 5 H2N mM) yl)thiophene-2- a sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (R) or (S)-4- Fluoro-N'- CHIRAL 30% of ((1,2,3 ,5,6,7-hexa-ART EtOH hydrodicyclopen-Cellulo- in Hex 422 678a ta[b,e]pyridin-8-se-SB, 439 (NH 3 .Meyl)carbamoyl)-5-(2-2* 25 OH 8 hydroxypropan-2-cm, 5 mM) yl)thiophene-2- a sulfonimidamide (R) or (S)-N'-((2-cyclobutyl-3-methyl-CHI-6,7-dihydro -5H- 30% RAL-cyclopen- EtOH HO PAK IG, 423 658b HN N ta[b]pyridin-4- in Hex 449

N 5*25 yl)carbamoyl)-4-(2-(0.1% S * SO cm, 5 O hydroxypropan-2- from FA) H 2 N an yl)thiophene-2-sulfonimidamide (S) or (R)- N'-((2-cyclobutyl-3-methyl-CHI-6,7-dihydro-5H-30% RAL-cyclopen-EtOH PAK IG, 424 658a ta[b]pyridin-4- in Hex 449 5 *25 yl)carbamoyl)-4-(2-(0.1% cm, 5 hydroxypropan-2- from FA) an yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((2- cyclopropyl-3-isopropyl-6,7-di-CHI- 30% HO hydro-5H-RAL-MeOH cyclopen-PAK ID, (NH 3 -425 667b HN N 463

N ta[b]pyridin-4- 2*25 MeOH 2 S * S O yl)carbamoyl)-4-(2-cm, 5 mM) in

The H2N hydroxypropan-2- a CO2 yl)thiophene-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((2-cyclopropyl-3-isopropyl-6,7-di - CHI- 30% hydro-5H-RAL-MeOH cyclopen-PAK ID, (NH 3 -426 667a 463 ta[b]pyridin-4-2*25 MeOH 2yl)carbamoyl)-4-(2-cm, 5 mM) in hydroxypropan-2-a CO 2 yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((2-(tert-butyl)-3-methyl-CHI-6,7-dihydro -5H- 30% RAL-cyclopen-EtOH PAK IF, 427,657b ta[b]pyridin-4- in Hex 451 2*25 yl)carbamoyl)-4-(2-(0.1% cm, 5 hydroxypropan- 2- from FA) an yl)thiophene-2-sulfonimidamide (S) or (R)-N'-((2-(tert-butyl)-3-methyl-CHI-6,7-dihydro-5H- 30% RAL-cyclopen-EtOH

HO

HN N PAK IF, 428 657a ta[b]pyridin-4- in Hex 451 N 2*25 yl)carbamoyl)-4-(2-(0.1% SSO cm, 5 H 2 N * The hydroxypropan-2- of FA ) an yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((2,3-dicyclopropyl-6,7-dihydro-5H-Chiral-30% cyclopenpak ID, EtOH

H 429 670b HO N ta[b]pyridin-4-2*25 in Hex 461 * N N S S yl)carbamoyl)-4-(2-cm, 5 (0.1%

O H2N O hydroxypropan-2-um from FA) yl)thiophene-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((2,3-dicyclopropyl-6,7-dihydro -5H- Chiral- 30% cyclopen-pak ID, EtOH

H 430 670a HO N ta[b]pyridin-4- 2*25 in Hex 461

N N S S yl)carbamoyl)-4-(2-cm, 5 (0.1%

The H 2 N O hydroxypropan-2-one of FA) yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((2.6-10% dicyclopropyl-3,5-Chiral-IPA in dimethylpyridin- 4- pak ID, Hex:DC

HO 431 612b HN N yl)carbamoyl)-4-(2- 2*25 M (3:1, 449 N hydroxypropan-2-cm, 5 NH 3 -S * SO H 2 N O yl)thiophene-2- a MeOH sulfonimidamide 10 mM) (S) or (R)-N'-((2.6-10% dicyclopropyl-3,5-Chiral-IPA in dimethylpyridin-4-pak ID, Hex:DC 432 612a yl)carbamoyl)-4 -(2-2*25M (3:1, 449 hydroxypropan-2-cm, 5 NH 3 -yl)thiophene-2- a 10 mM MeOH sulfonimidamide) (R) or (S)-N'-((2- cyclopropyl-3-methyl-CHI- 10% 6,7-dihydro-5H-RAL-EtOH HO cyclopen-

HN N PAK IG, at 433 626b N ta[b]pyridin-4- 436 N 20*250 MTBE

S yl)carbamoyl)-4-(2- * SO mm, 5 (0.1% O hydroxypropan-2-H 2 N one of FA) yl)thiazol-2-sulfonimidamide (S) or (R)-N'-( (2-cyclopropyl-3-methyl-CHI- 10% 6,7-dihydro-5H-RAL-EtOH cyclopen-PAK IG, at 434 626a ta[b]pyridin-4-436 20*250 MTBE yl) carbamoyl)-4-(2-mm, 5 (0.1% hydroxypropan-2-one from FA)yl)thiazol-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-N'-((2-(cyclopropylmethyl)-3-methyl-6,7 -di-CHI- 30% hydro-5H-RAL-HO EtOH

HN N cyclopen-PAK IG, 435 665b in Hex 449 * N ta[b]pyridin-4- 2*25 SSO (0.1% Oyl)carbamoyl)-4-(2-cm, 5 H 2 N FA) hydroxypropan -2- an yl)thiophene-2-sulfonimidamide (S) or (R)-N'-((2-(cyclopropylmethyl)-3-methyl-6,7-di-CHI- 30% hydro-5H-RAL - EtOH cyclopen-PAK IG, 436 665a in Hex 449 ta[b]pyridin-4-2*25 (0.1% yl)carbamoyl)-4-(2-cm, 5 of FA) hydroxypropan-2-yl )thiophene-2-sulfonimidamide (R) or (S)-N'-((3-cyclopropyl-2-ethyl-CHI-6,7-dihydro-5H-30% RAL-HO cyclopen-EtOH PAK IG , 437 654b HN N ta[b]pyridin-4- in Hex 449 N 2*25

S yl)carbamoyl)-4-(2-(0.1% * SO cm, 5 H 2 N O hydroxypropan-2- from FA) an yl)thiophene-2-sulfonimidamide (S) or (R)-N'-( (3-cyclopropyl-2-ethyl-CHI-6,7-dihydro-5H- 30% RAL-

HO cyclopen- EtOH PAK IG, 438 654a HN N ta[b]pyridin-4- in Hex 449 N 2*25

S yl)carbamoyl)-4-(2-(0.1% * S0 cm, 5 H 2 N O hydroxypropan-2- from FA) an yl)thiophene-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-1-ethyl-N'-(((R)-3-methyl-CHI - 50% 1,2,3,5,6,7-hexa-RAL-EtOH hydrodicyclopen-PAK IE, in Hex 439 634b 389 ta[b,e]pyridin-8-2*25 (NH3.Meyl) carbamoyl)-1H-cm, 5OH 8 pyrazol-3-one mM)sulfonimidamide (S) or (R)-1-ethyl-(R)N'-(((R)-3-methyl-CHI- 50% of abs 1,2,3,5,6,7-hexa-RAL-EtOH HN N hydrodicyclopen-PAK IE, in Hex 440 634a 389 NN ta[b,e]pyridin-8-2*25 (NH3.Me

NSO * O yl)carbamoyl)-1H- cm, 5 OH 8 H 2 N pyrazol-3-one mM)sulfonimidamide (R) or (S)-1-Methyl-N'-(((R)-3-methyl- CHI-50% 1,2,3,5,6,7-hexa-RAL-EtOH hydrodicyclopen-PAK IE, in Hex 441 639b 375 ta[b,e]pyridin-8-2*25 (NH 3 .Meyl )carbamoyl)-1H-cm, 5OH 8 pyrazol-3-one mM)sulfonimidamide (S) or (R)-1-Methyl-N'-(((R)-3-methyl-CHI- 50% of 1 ,2,3,5,6,7-hexa-RAL-EtOH hydrodicyclopen-PAK IE, in Hex 442 639a 375 ta[b,e]pyridin-8-2*25 (NH 3 .Meyl)carbamoyl)-1H- cm, 5 OH 8 pyrazol-3-one mM)sulfonimidamide (R) or (S)-N'-(((R)- 20% 3-methyl-1,2,3,5,6,7-CHI - EtOH hexa-RAL- in hydrodicyclopen-PAK IE, 443 700b MTBE 437 ta[b,e]pyridin-8-2*25 (NH3-yl)carbamoyl)-1-cm, 5 MeOH phenyl-1H-pyrazol-3 - a 10 mM) sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-(((R)- 20% 3-methyl-1, 2,3,5,6,7-CHI-EtOH hexa-RAL- in hydrodicyclopen-PAK IE, 444 700a MTBE 437 ta[b,e]pyridin-8- 2*25 (NH 3 -yl)carbamoyl)-1- cm, 5 MeOH phenyl-1H-pyrazol-3- a 10 mM)sulfonimidamide (S) or (R)-1-(Difluoromethyl)-N'-((1',5',6',7'-tetra- 638b hydro-2'H-CHI- 5%

F F spiral-IPA in N HN N ro[cyclopropane-PAK IG, MTBE 445 423 N N 1,3'- 5*25 (NH 3 - * S O dicyclopen-cm, 5 MeOH

The H 2 N ta[b,e]pyridin]-8'- a 10 mM)yl)carbamoyl)-1H-pyrazol-4-sulfonimidamide (R) or (S)-1-(Difluoromethyl)-N'-(( 1',5',6',7'-tetrahydro-2'H-CHI- 5% spiral-IPA in ro[cyclopropane-PAK IG, MTBE 446 638a 423 1,3'- 5*25 (NH 3 -dicyclopen-cm, 5 MeOH ta[b,e]pyridin]-8'- a 10 mM) yl)carbamoyl)-1H-pyrazol-4-sulfonimidamide (S) or (R)-1-(Difluoromethyl) -N'-CHI- 3% ((3,3-dimethyl-RAL-IPA in 1,2,3,5,6,7-hexa-PAK IG, MTBE 447 637b hydrodicyclopen-425 5*25 (NH 3 - ta[b,e]pyridin-8-cm, 5 MeOH yl)carbamoyl)-1H- a 10 mM) pyrazol-4-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (R) or (S)-1-FF (Difluoromethyl)-N'-N CHI- 3% of (( 3,3-dimethyl-RAL-IPA in N 1,2,3,5,6,7-hexa-N PAK IG, MTBE 448 637a hydrodicyclopen-425 5*25 (NH3-ta[b,e]pyridin-8 - N NH cm, 5 MeOH * Syl)carbamoyl)-1H-H 2 N a 10 mM) OO pyrazol-4-sulfonimidamide (S) or (R)-3-Fluoro-5-(2-hydroxypropan-2-yl) - CHIRAL 30% N'-((2-isopropyl-3-ART EtOH methyl-6,7-dihydro-Cellulo- in Hex 449 645b 5H-se-SB, 455 (NH3.Me cyclopen-2*25 OH 8 ta[b]pyridin-4-cm, 5mM)yl)carbamoyl)thiophenone o-2-sulfonimidamide (R) or (S)-3-Fluoro-5-(2-hydroxypropan-2-yl)- CHIRAL 30% F H2 NO N'-((2-isopropyl-3-ART S * O EtOH methyl-6,7-dihydro-Cellulo-N in Hex 450 645a N 5H-se-SB, 455 SN ( NH3.Me H cyclopen-2*25 OH 8 OH ta[b]pyridin-4-cm, 5 mM) yl)carbamoyl)thiophene an o-2-sulfonimidamide (R) or (S)-1-Isopropyl-N' -((2-CHI-20% isopropyl-3-methyl-RAL-EtOH 6,7-dihydro-5H-PAK IG, in Hex 451 644b cyclopen-405 2*25 (NH3.Me t a[b]pyridin-4-cm, 5OH 8yl)carbamoyl)-1H-one mM) pyrazol-3-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-1- Isopropyl-N'-((2- CHI- 20% isopropyl- 3-methyl-H2N O RAL-EtOH O 6,7-dihydro-5H-S PAK IG, in Hex 452 644a N * NN cyclopen- 405 NN 2*25 (NH3.Me H ta[b]pyridin-4 - cm, 5 OH 8 yl)carbamoyl)-1H-one mM) pyrazol-3-sulfonimidamide (R) or (S)-N'-((1,2,3,5,6,7-hexa- 50% of Chiral-hydrodicyclopen-IPA in pak ID, ta[b,e]pyridin-8-Hex 453 633b 2*25 415 yl)carbamoyl)-4-(2-(NH 3 .Me cm, 5 hydroxypropan-2-OH 8 a mM yl)benzenesulfonyl)midamide (S) or (R)-N'-OH ((1,2,3,5,6,7-hexa-50% Chiral-hydrodicyclopen-IPA in pak ID, H ta[ b,e]pyridin-8-Hex 454 633a N 2*25 415 * NN yl)carbamoyl)-4-(2-(NH 3 .Me S cm, 5 H 2 N OO hydroxypropan-2-OH 8 um yl)benzenesulfonyl mM) midamide (R) or (S)-N'-((1,2,3,5,6,7-hexa-CHI-50% hydrodicyclopen-RAL-EtOH ta[b,e]pyridin-8-PAK IG , in Hex 455 625b 415 yl)carbamoyl)-3-(2-20*250 (NH 3 .Me hydroxypropan-2-mm, 5 OH 8 yl)benzenesulfonyl mM) midamide (S) or (R) -N'- ((1,2,3,5,6,7-hexa-CHI- 50% of

OH hydrodicyclopen-RAL-EtOH HN N ta[b,e]pyridin-8-PAK IG, in Hex 456 625a 415 N yl)carbamoyl)-3-(2-20*250 (NH 3 .Me SO hydroxypropan-2-mm , 5 OH 8 * O (yl)benzenesulfonymum mM) H2N midamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-3-Fluoro-5-(2-hydroxypropan-2-yl)-CHI- N'-((3-methyl-2-10% RAL-(trifluoromethyl)-6,7-IPA in PAK ID, 457 632b dihydro-5H-MTBE 481 2*25 cyclopen- (0.1% cm , 5 ta[b]pyridin-4- from FA) an yl)carbamoyl)thiopheno-2-sulfonimidamide (R) or (S)-3-Fluoro-5-(2-hydroxypropan-2-yl)-F CHI - F N'-((3-methyl-2- 10% of

F RAL-(trifluoromethyl)-6,7-IPA in F PAK ID, 458 632a HN N dihydro-5H-MTBE 481 N 2*25 cyclopen- (0.1%

OH SSO cm, 5 * The ta[b]pyridin-4- of FA) H 2 N is an yl)carbamoyl)thiopheno-2-sulfonimidamide (R) or (S)-4-(2-hydroxypropan-2-yl)- N'-((3-methyl-2-CHI- 20% (trifluoromethyl)-6,7-RAL-EtOH dihydro-5H-PAK IG, 459 624b in Hex 463 cyclopen-2*25 (0.1 % ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiophene an o-2-sulfonimidamide (S) or (R)-4-(2-hydroxypropan-2-yl)-FF N'- ((3-methyl-2-CHI- 20% OH F (trifluoromethyl)-6,7-RAL-EtOH dihydro-5H-PAK IG, 460 624a HN N in Hex 463 N cyclopen-2*25 (0 .1% SSO ta[b]pyridin-4-cm, 5 * O of FA) H 2 N yl)carbamoyl)thiophen an o-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (R) or (S)-N'-((3-cyclopropyl-2-ethyl-6,7-di -hydro-5H-CHI- 30% cyclopen-RAL-EtOH

F

HN N ta[b]pyridin-4-PAK IC, 461 631b in Hex 467 N yl)carbamoyl)-3-2*25

S (0.1%

OH S

OO fluoro-5-(2-cm, 5H 2N * of FA)hydroxypropan-2-umyl)thiophene-2-sulfonimidamide (S) or (R)-N'-((3-cyclopropyl-2-ethyl- 6,7-dihydro-5H-CHI- 30% cyclopen-RAL-EtOH ta[b]pyridin-4-PAK IC, 462,631a in Hex 467 yl)carbamoyl)-3-2*25 (0.1 % fluoro-5-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiophene-2-sulfonimidamide (R) or (S)-N'-((3-cyclopropyl-2-ethyl-CHI-6) ,7-dihydro-5H- 30% RAL-cyclopen-EtOH

N HN N PAK IC, 463 630b ta[b]pyridin-4- in Hex 450 N 2*25

S yl)carbamoyl)-2-(2-(0.1% OH * SO cm, 5 O hydroxypropan-2- from FA) H 2 N an yl)thiazol-5-sulfonimidamide (S) or (R)-N' -((3-cyclopropyl-2-ethyl-CHI-6,7-dihydro-5H- 30% RAL-cyclopen-EtOH PAK IC, 464 630a ta[b]pyridin-4- in Hex 450 2*25 yl)carbamoyl)-2-(2-(0.1% cm, 5-hydroxypropan-2- from FA) an yl)thiazol-5-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((3-cyclopropyl-2-methyl-CHIRAL 10% of 6 ,7-dihydro-5H-ART OH EtOH cyclopen-Cellulo- at 465 623b HN N ta[b]pyridin-4-se-SB, 435

MTBE N yl)carbamoyl)-4-(2-2*25

SSO (0.1% * hydroxypropan-2-cm, 50 of FA) H 2 N yl)thiophene-2- a sulfonimidamide (R) or (S)-N'-((3-cyclopropyl-2-methyl-CHIRAL 10) % 6,7-dihydro-5H-ART EtOH cyclopen-Cellulo- at 466 623a ta[b]pyridin-4-se-SB, 435

MTBE yl)carbamoyl)-4-(2-2*25 (0.1% hydroxypropan-2-cm, 5 of FA)yl)thiophene-2- a sulphonimide (R) or (S)-4-(2- hydroxypropan-2-yl)-N'-((3-isopropyl-2-CHI- 50% OH methyl-6,7-dihydro-RAL-IPA in HN N 5H-PAK IC, 467 622b MTBE 437 N cyclopen-2*25 (0.1% SSO ta[b]pyridin-4-cm, 5*O of FA) H 2 N yl)carbamoyl)thiophene an o-2-sulfonimidamide (S) or (R)-4-( 2-hydroxypropan-2-yl)-N'-((3-isopropyl-2-CHI- 50% methyl-6,7-dihydro-RAL-IPA in 5H-PAK IC, 468 622a MTBE 437 cyclopen- 2*25 (0.1% ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiophene an o-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure IUPAC Name Column tes [M+H]+ Final (R) or (S)-1-(Difluoromethyl)-N'-FF ((3-methyl-2- CHI - 20% of

F (trifluoromethyl)-6,7-RAL-MeOH F dihydro-5H-PAK IG, (NH 3 - 469 621b HN N 439 NN cyclopen-2*25 MeOH 2 FN * SO ta[b]pyridin-4-cm , 5 mM) in

The H 2 Nyl)carbamoyl)-1H- is a CO 2 pyrazol-3-sulfonimidamide (S) or (R)-1-(Difluoromethyl)-N'-((3-methyl-2-CHI- 20% of (trifluoromethyl) -6,7-RAL-MeOH dihydro-5H-PAK IG, (NH 3 -470 621a 439 cyclopen-2*25 MeOH 2 ta[b]pyridin-4-cm, 5 mM) in yl)carbamoyl)-1H - a CO2 pyrazol-3-sulfonimidamide (R) or (S)-N'-((3-cyclopropyl-2-methyl-CHI-6,7-dihydro-5H- 30% RAL-cyclopen-EtOH PAK IC, 471 618b N HN N ta[b]pyridin-4- in Hex 436 N 2*25 yl)carbamoyl)-5-(2-(0.1%

OH S * SO cm, 5 O hydroxypropan-2- from FA) H 2 N an yl)thiazol-2-sulfonimidamide (S) or (R)-N'-((3-cyclopropyl-2-methyl-CHI-6,7 -dihydro-5H- 30% RAL-cyclopen-EtOH PAK IC, 472 618a ta[b]pyridin-4- in Hex 436 2*25 yl)carbamoyl)-5-(2-(0.1% cm , 5-hydroxypropan-2- from FA) an yl)thiazol-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-1- Isopropyl-N'-((3-Methyl-2-CF3 Chiral- 30% (trifluoromethyl)-6,7-pak ID, EtOH HN N dihydro-5H- 473 628b NN 2*25 in Hex 431 cyclopen- N * SO cm, 5 (0.1% O ta[b] pyridin-4-H 2 N one of FA)yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (S) or (R)-1-Isopropyl-N'-((3-methyl-2-Chiral- 30% of (trifluoromethyl)-6,7-pak ID, EtOH dihydro-5H- 474 628a 2*25 in Hex 431 cyclopen-cm, 5 (0.1% ta[b]pyridin-4-um from FA) yl) carbamoyl)-1H-pyrazol-3-sulfonimidamide (S) or (R)-1-(Difluoromethyl)-N'-

CHIRAL F CF3 ((3-methyl-2-ART 25% F(trifluoromethyl)-6,7-Cellulo-EtOH N HN N dihydro-5H- 475 617b NN se-SB, in Hex 439 cyclopen- * SO 2*25 (0.1% O ta[b]pyridin-4-H 2 N cm, 5 of FA)yl)carbamoyl)-1H- a pyrazol-4-sulfonimidamide (R) or (S)-1-(Difluoromethyl) -N'-

CHIRAL ((3-methyl-2-ART 25% (trifluoromethyl)-6,7-Cellulo-EtOH dihydro-5H- 476 617a se-SB, in Hex 439 cyclopen-2*25 (0.1% rt [b]pyridin-4-cm, 5 of FA)yl)carbamoyl)-1H- a pyrazol-4-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-N'-((3-ethyl-2-(trifluoromethyl)-6,7 - CHI-CF3 15% dihydro-5H-RAL-EtOH N HN N cyclopen-PAK IE, 477 610b N in Hex 478 ta[b]pyridin-4-2*25

OH S * SO (0.1% Oyl)carbamoyl)-2-(2-cm, 5 H 2 N of FA)hydroxypropan-2-umyl)thiazol-5-sulfonimidamide (R) or (S)-N'- ((3-ethyl-2-(trifluoromethyl)-6,7-CHI- 15% dihydro-5H-RAL-EtOH cyclopen-PAK IE, 478 610a in Hex 478 ta[b]pyridin-4-2* 25 (0.1% yl)carbamoyl)-2-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiazol-5-sulfonimidamide (R) or (S)-N'-((3-ethyl) -2-(trifluoromethyl)-6,7-CHI-CF3 dihydro-5H- 20% RAL-F cyclopen-EtOH HN N PAK IF, 479 611b N ta[b]pyridin-4- in Hex 495 4, 6*50

OH S * SO yl)carbamoyl)-3-(0.1% 0 mm, 3 H 2 N fluoro-5-(2- from FA) a hydroxypropan-2-yl)thiophene-2-sulfonimidamide (S) or (R) -N'-((3-ethyl-2-(trifluoromethyl)-6,7-CHI-dihydro-5H- 20% RAL-cyclopen-EtOH PAK IF, 480 611a ta[b]pyridin-4- in Hex 495 4.6*50 yl)carbamoyl)-3-(0.1% mm, 3-fluoro-5-(2-from FA) a hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-N'-((3-ethyl-2-(trifluoromethyl)-6,7 - CHI- 20% H2N dihydro-5H-RAL-EtOH

H * S N N CF3 cyclopen-PAK IG, in Hex 481 698b 477 O O N ta[b]pyridin-4- 2.0*25 (NH3.Me

HO Sil)carbamoyl)-4-(2-cm, 5 OH 8 hydroxypropan-2-one mM)yl)thiophene-2-sulfonimidamide (S) or (R)-N'-((3-ethyl-2- (trifluoromethyl)-6,7-CHI- 20% dihydro-5H-RAL-EtOH cyclopen-PAK IG, in Hex 482 698a 477 ta[b]pyridin-4-2.0*25 (NH 3 .Meyl )carbamoyl)-4-(2-cm, 5 OH 8 hydroxypropan-2-one mM)yl)thiophene-2-sulfonimidamide (S) or (R)-4-Fluoro-5-(2-

CHIRAL hydroxypropan-2-yl)- 30% of

F ART (R) N'-(((R)-3-methyl-EtOH abs Cellulo-

H

N 1,2,3,5,6,7-hexa- in Hex 483 616b HO SN se-SB, 453 SN hydrodicyclopen-(NH3.Me H2N * OO 2*25 ta[b,e]pyridin-8-OH 8 cm, 5 yl)carbamoyl)thio-mM) a phen-2-sulfonimidamide (R) or (S)-4-Fluoro-5-(2-

CHIRAL hydroxypropan-2-yl)- 30% of

ART N'-(((R)-3-Methyl-EtOH Cellulo-1,2,3,5,6,7-hexa- in Hex 484 616a se-SB, 453 hydrodicyclopen-(NH 3 .Me 2*25 rt [b,e]pyridin-8-OH 8 cm, 5 yl)carbamoyl)thio- mM) a phen-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (S) or (R)-4-Fluoro-5-(2-hydroxypropan-2-yl)-CHIRAL 30 % N'-((1',5',6',7'-tetra-ART F EtOH hydro-2'H-Cellulo-HN in Hex 485 614b N spiro[cyclose-SB, 465 N (NH 3 .Me OH S * SO propane-1,3'-dicy-2*25 O OH 8 H 2 N clopenta[b,e]pi-cm, 5 mM) ridin]-8'-yl)carba- a moyl)thiophene- 2-sulfonimidamide (R) or (S)-4-Fluoro-5-(2-hydroxypropan-2-yl)-

CHIRAL N'-((1',5',6',7'-tetra- 30% of

ART hydro-2'H-EtOH Cellulospiro[cyclo-in Hex 486 614a se-SB, 465 propane-1,3'- (NH3.Me 2*25 dicyclopen-OH 8 cm, 5 ta[b,e] pyridin]-8'-mM) an yl)carbamoyl)thiophene-2-sulfonimidamide -N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-CHIRAL

F hydrodicyclopen-ART 40% H ta[b,e]pyridin-8-Cellulo-EtOH

N 487 613b HO S * N yl)carbamoyl)-4-se-SB, in Hex 467

No

S H2N OO fluoro-5-(2-2*25 (0.1% hydroxypropan-2-cm, 5 of FA)yl)thiophene-2- a sulfonimidamide (R) or (S)-N'-((3) ,3-dimethyl-1,2,3,5,6,7-

CHIRAL hexa-ART 40% hydrodicyclopen-Cellulo-EtOH ta[b,e]pyridin-8-488,613ase-SB, in Hex 467 (yl)carbamoyl)-4-2*25 (0.1% fluoro-5- (2-cm, 5 of FA) hydroxypropan-2-anyl)thiophene-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-N'-((3,3-dimethyl-1,2,3,5) ,6,7- HIRAL- 30% of

N hexa- H PAK ID, EtOH

NNN hydrodicyclopen-489 697b 2*25 in Hex 403 SN ta[b,e]pyridin-8-H 2 N * O0 cm, 5 (0.1% yl)carbamoyl)-1-ethyl-one of FA) 1H-pyrazol- 3-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-HIRAL-30% hexa-PAK ID, EtOH hydrodicyclopen- 490 697a 2 *25 in Hex 403 ta[b,e]pyridin-8-cm, 5 (0.1% yl)carbamoyl)-1-ethyl-one of FA) 1H-pyrazol-3-sulfonimidamide (R) or (S) -4-(2-hydroxypropan-2-yl)-F3C N'-((2-(2,2,2-CHI-30% OH trifluoroethyl)-6,7-di-RAL-IPA in HN N hydro -5H-PAK IC, 491 607b Hex 463 N cyclopen-2*25 (0.1% S * SO ta[b]pyridin-4-cm, 5 O of FA) yl)carbamoyl)thiophenone H 2 N o-2 - sulfonimidamide (S) or (R)-4-(2-hydroxypropan-2-yl)-N'-((2-(2,2,2-CHI-30% trifluoroethyl)-6,7-di- RAL-IPA in hydro-5H-PAK IC, 492 607a Hex 463 cyclopen-2*25 (0.1% ta[b]pyridin-4-cm, 5 of FA) yl)carbamoyl)thiophen an o-2-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-5-((Dimethylamino-15% no)methyl)-3-fluoro- CHI-EtOH FH 2N (R) N'-(((R)-3-methyl-RAL- in abs * SOH 1,2,3,5,6,7-hexa-PAK IG, Hex:DC

N 493 636b Y N N 452

N-hydrodicyclopen- 2.0*25M (3:1,

Ta[b,e]pyridin-8-cm, 5 NH 3 -yl)carbamoyl)thiophen is an o-2- 10 mM MeOH)sulfonimidamide (S) or (R)-5-((Dimethylamylamyl-15% no) methyl)-3-fluoro-CHI-EtOH N'-(((R)-3-methyl-RAL- in 1,2,3,5,6,7-hexa-PAK IG, Hex:DC 494 636a 452 hydrodicyclopen - 2.0*25 M (3:1, ta[b,e]pyridin-8-cm, 5 NH 3 -yl)carbamoyl)thiophen a MeOH o-2- 10 mM)sulfonimidamide (R) or (S)- N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-CHI- 10% hydrodicyclopen-RAL-IPA in ta[b,e]pyridin-8-PAK ID, 495 304b MTBE 431 yl)carbamoyl)-6,7-2*25 (0.1% dihydro-5H-cm, 5 of FA) pyrazolo[5,1-um b][1,3]oxazine-3- (S) or (R)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-CHI-10% sulfonimidamide)

The hydrodicyclopen- RAL- N H IPA in

NN ta[b,e]pyridin-8-PAK ID, 496 304a MTBE 431 NN yl)carbamoyl)-6,7- 2*25 * S (0.1% O dihydro-5H-cm, 5 O of FA) H2N pyrazolo[5,1-um b][1,3]oxazine-3-sulfonimidamide

Number- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Columns [M+H]+ Final (R) or (S)-N'-((2-cyclopropyl-3-methyl- 10% of 6, 7-dihydro-5H-CHI-MeOH cyclopen-RAL- in ta[b]pyridin-4-PAK IC, 497 306b MTBE 417 yl)carbamoyl)-6,7-2*25 (NH 3 -dihydro- 5H-cm, 5 MeOH pyrazolo[5,1-um 10 mM) b][1,3]oxazine-3-sulfonimidamide (S) or (R)-N'-((2-cyclopropyl-3-methyl-10) % 6,7-dihydro-5H-CHI-MeOH cyclopen-RAL- in ta[b]pyridin-4-PAK IC, 498 306a MTBE 417 yl)carbamoyl)-6,7-2*25 (NH 3 - dihydro-5H-cm, 5 MeOH pyrazolo[5,1-um 10 mM) b][1,3]oxazine-3-sulfonimidamide (R,S) or (S,S)-2-(1,2 -dihydroxypropan-2-yl)-

CHIRAL N'-((3-methyl-2-ART 30% (trifluoromethyl)-6,7-Cellulo-EtOH dihydro-5H-499 605e se-SB, in Hex 480 cyclopen-2*25 (0. 1% ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiazol-a 5-sulfonimidamide (from Ex. 241) (R,R) or (S,R)-2-(1 ,2-dihydroxypropan-2-yl)-

CHIRAL N'-((3-methyl-2-ART 30% (trifluoromethyl)-6,7-Cellulo-EtOH dihydro-5H- 500 605c se-SB, in Hex 480 cyclopen-2*25 (0. 1% ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiazole-a 5-sulfonimidamide (from Ex. 241)

No.- Eluent- LC-MS Ex. No. Target Structure Name IUPAC Column tes [M+H]+ Final (S, S) or (R, S)-2-(1,2-dihydroxypropan-2-yl )-

CHIRAL N'-((3-methyl-2-ART 30% (trifluoromethyl)-6,7-Cellulo-EtOH 605g dihydro-5H-501se-SB, in Hex 480 cyclopen-2*25 (0. 1% ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiazol-a 5-sulfonimidamide (from Ex. 242) (S,R) or (R,R)-2-(1 ,2-dihydroxypropan-2-yl)-

CHIRAL N'-((3-methyl-2-ART 30% (trifluoromethyl)-6,7-Cellulo-EtOH dihydro-5H- 502 605h se-SB, in Hex 480 cyclopen-2*25 (0. 1% ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiazole-a 5-sulfonimidamide (from Ex. 242)

[002621] Table 39. The examples in the following table were obtained from chiral HPLC resolutions of racemic examples. The chiral column and eluents are listed in the table. By convention, the fastest-eluting diastereoisomer or isomer is always listed first in the table followed by the second-fastest-eluting enantiomer in the mixture, and so on. The symbol * in a chiral center denotes that the chiral center has been separated, and the absolute stereochemistry at that chiral center has not been determined. The stereochemistry assigned in compound names is provisional.

Number- Ex.

LC-MS ro Target Structure IUPAC Name Column Eluents # [M+H]+ Final (R, R) or (S, R) or (R, S) or (S, S)-1- 50% Isopropyl-N '-((3-CHI-EtOH:C methyl-1,2,3,5,6,7-RAL-AN (2:1, hexa-PAK IA, 503 660d NH 3 - 403 hydrodicyclopen- 5*25 MeOH 2 ta[b,e]pyridin-8-cm, 5 mM) in yl)carbamoyl)-1H- a CO 2 imidazole-4-sulfonimidamide (S, R) or (R, S) or (S, S) or (R , R)-1- 50% Isopropyl-N'-((3-CHI-EtOH:C methyl-1,2,3,5,6,7-RAL-AN (2:1, hexa-PAKIA, 504 660c NH 3 - 403 hydrodicyclopen- 5*25 MeOH 2 ta[b,e]pyridin-8-cm, 5 mM) in yl)carbamoyl)-1H- a CO 2 imidazol-4-sulfonimidamide (S, S) or (R , S) or (S, R) or (R, R)-1- 50% Iisopropyl-N'-((3-CHI-EtOH:C methyl-1,2,3,5,6,7-RAL - AN (2:1, hexa-PAK IA, 505 660b NH 3 - 403 hydrodicyclopen- 5*25 MeOH 2 ta[b,e]pyridin-8-cm, 5 mM) in yl)carbamoyl)-1H- a CO 2 imidazole -4-sulfonimidamide (R,S) or (S,S) or (S,R) or (R,R)-1- 50% Iisopropyl-N'-((3-CHI-EtOH:C methyl-1 ,2,3,5,6,7-RAL-AN (2:1, hexa-PAK IA, 506 660a NH3-403 hydrodicyclopen- 5*25 Me OH 2 ta[b,e]pyridin-8-cm, 5 mM) in yl)carbamoyl)-1H- a CO 2 imidazol-4-sulfonimidamide

Number- Ex. LC-MS ro Target Structure Name IUPAC Column Eluents # [M+H]+ Final (R, S) and (S, S) or (S, R) and (R, R)-2- (1 ,2-di-

CHIRAL hydroxypropan-2-yl)- 40% of

ART N'-((3,3-dimethyl-EtOH Cellulo-1,2,3,5,6,7-hexa-(NH 3 - 507 201f se-SB, 466 hydrodicyclopen-MeOH 2 2*25 ta[b, e]pyridin-8-mM) in two diastereomers, most likely 5-yl)carbamoyl)thiazole-CO2 probably with the same confi- a 5-sulfonimidamide guration in sulfur (mixture of two isomers) (R, R) and (S, R) or (R, S) and (S, S)-2-(1,2-di-

CHIRAL hydroxypropan-2-yl)- 40% of

ART N'-((3,3-dimethyl-EtOH Cellulo-1,2,3,5,6,7-hexa-(NH 3 - 508 201e se-SB, 466 hydrodicyclopen-MeOH 2 2*25 ta[b, e]pyridin-8-mM) in two diastereomers, most likely 5-yl)carbamoyl)thiazole-CO2 probably with the same confi- a 5-sulfonimidamide guration in sulfur (mixture of two isomers) (R,S) or (S, S) or (S, R) or (R, R)-2-(1,2-dihydroxypropan-2-yl)-CHI- 30% N'-((3,3-dimethyl- RAL-EtOH 1,2,3,5,6,7-hexa-PAK IF, 509 201d in Hex 466 hydrodicyclopen-2*25 (0.1% ta[b,e]pyridin-8-cm, 5 of FA ) yl)carbamoyl)thiazol-a 5-sulfonimidamide (from Ex. 507)

Number- Ex. LC-MS ro Target Structure Name IUPAC Column Eluents # [M+H]+ Final (S, S) or (R, S) or (S, R) or (R, R)-2- (1 ,2-dihydroxypropan-2-yl)-CHI- 30% N'-((3,3-dimethyl-RAL-EtOH 1,2,3,5,6,7-hexa-PAK IF, 510 201c in Hex 466 hydrodicyclopen-2*25 (0.1% ta[b,e]pyridin-8-cm, 5 of FA)yl)carbamoyl)thiazole-a 5-sulfonimidamide (from Ex. 507) (R, R) or (S, R) or (R, S) or (S, S)-2-(1,2-di-H2N

CHIRAL hydroxypropan-2-yl)- * S O ART 30% of

NO N'-((3,3-dimethyl-SN Cellulo-EtOH 1,2,3,5,6,7-hexa- 511 201a * HN se-SB, in Hex 466 HO hydrodicyclopen-N 2*25 (0 .1% HO ta[b,e]pyridin-8-cm, 5 of FA)yl)carbamoyl)thiazol-a 5-sulfonimidamide (from Ex. 508) (S,R) or (R,R) or (R, S) or (S, S)-2-(1,2-di-H2N

CHIRAL hydroxypropan-2-yl)- * S O ART 30% of

NO N'-((3,3-dimethyl-SN Cellulo-EtOH 1,2,3,5,6,7-hexa- 512 201b * HN se-SB, in Hex 466 HO hydrodicyclopen-N 2*25 (0 .1% HO ta[b,e]pyridin-8-cm, 5 of FA)yl)carbamoyl)thiazol-a 5-sulfonimidamide (from Ex. 508)

Number- Ex. LC-MS ro Target Structure IUPAC Name Column Eluents No. [M+H]+ Final (S, S) and (S, R) or (R, S) and (R, R)-N'- ( (3-ethyl-1,2,3,5,6,7-

CHIRAL hexa-ART 30% hydrodicyclopen-Cellulo-EtOH ta[b,e]pyridin-8- 513 662c se-SB, in Hex 450 yl)carbamoyl)-2-(2-2*25 (0.1% hydroxypropan -2- cm, 5 of FA)yl)thiazol-5- a sulfonimidamide (mixture of two isomers) (R,R) or (R,S) or (S,R) or (S,S)-N'-

CHIRAL ((3-ethyl-1,2,3,5,6,7-ART 30% hexa-Cellulo-EtOH hydrodicyclopen-662dse-SB, in Hex 450 ta[b,e]pyridin-8-2 *25 (0.1% yl)carbamoyl)-2-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiazol-5-sulfonimidamide (R, S) or (R, R) or (S, R) or (S, S)-N'-

CHIRAL ((3-ethyl-1,2,3,5,6,7-ART 30% hexa-Cellulo-EtOH hydrodicyclopen-662dse-SB, in Hex 450 ta[b,e]pyridin-8-2 *25 (0.1% yl)carbamoyl)-2-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiazol-5-sulfonimidamide (S, R) or (S, S) or (R, S) or (R,R)-N'-((3-ethyl-10% CHI-1,2,3,5,6,7-hexa-EtOH RAL-hydrodicyclopen- in PAK IG, 516 662b ta[ b,e]pyridin-8-MTBE 450 2.0*25 yl)carbamoyl)-2-(2-(NH 3 -cm, 5 hydroxypropan-2-MeOH umyl)thiazol-5-10 mM)sulfonimidamide (from of Ex. 513)

Number- Ex. LC-MS ro Target Structure Name IUPAC Column Eluents # [M+H]+ Final (S, S) or (S, R) or (R, S) or (R, R)-N'-( (3-ethyl-10% CHI-1,2,3,5,6,7-hexa-EtOH * RAL-hydrodicyclopen- in N PAK IG, 517 662a NH2 ON ta[b,e]pyridin-8-MTBE 450 HO * 2.0 * 25 SS yl)carbamoyl)-2-(2-(NH3-

ONN cm, 5 H hydroxypropan-2-MeOH an yl)thiazol-5-10 mM)sulfonimidamide (from Ex. 513) (R, S) and (S, S) or (S, R) and (R, R)-5-(1,2-dihydroxypropan-2-yl)-CHIRAL N'-((3,3-dimethyl-ART 30% 1,2,3,5,6,7-hexa-Cell - EtOH 518 699c hydrodicyclopense-SB, in Hex 483 ta[b,e]pyridin-8-2*25 (0.1% two diastereomers, plus pro-yl)carbamoyl)-3-cm, 5 FA) ally with the same confi-fluorothiophene-2- a guration in sulfur sulfonimidamide (mixture of two isomers) (S, R) and (R, R) or (R, S) and (S, S)-5-(1, 2-dihydroxypropan-2-yl)-CHIRAL N'-((3,3-dimethyl-ART 30% 1,2,3,5,6,7-hexa-Cellulo-EtOH 519,699b hydrodicyclopenes- SB, in Hex 483 ta[b,e]pyridin-8-2*25 (0.1% two diastereomers, plus pro-yl)carbamoyl)-3-cm, 5 of FA) presumably with the same confi-fluorothiophene- 2- a guration in sulfur sulfonimidamide (mixture of two isomers)

Number- Ex.

LC-MS ro Target Structure IUPAC Name Column Eluents # [M+H]+ Final (S, S) or (R, S) or (S, R) or (R, R)-5-(1,2-di - 35% hydroxypropan-2-yl)-CHI-MeOH:A N'-((3,3-dimethyl-RAL-CN (2:8, 1,2,3,5,6,7-hexa-PAK) IG, 520 699a 0.1% 483 hydrodicyclopen-20*250 NH 3 .H 2 O ta[b,e]pyridin-8-mm, 5 ) in yl)carbamoyl)-3- a CO 2 fluorothiophene-2-sulfonimidamide (from from Ex. 518) (R, S) or (S, S) or (S, R) or (R, R)-5-(1,2-di-35% hydroxypropan-2-yl)-CHI- MeOH:A N'-((3,3-dimethyl-RAL-CN (2:8, 1,2,3,5,6,7-hexa-PAK IG, 521 640c 0.1% of 483 hydrodicyclopen-20 *250 NH 3 .H 2 O ta[b,e]pyridin-8-mm, 5 ) in yl)carbamoyl)-3- a CO 2 fluorothiophene-2-sulfonimidamide (from Ex. 518) (S, R) or (R , R) or (R, S) or (S, S)-5-(1,2-di-CHI- 40% hydroxypropan-2-yl)-RAL-MeOH:A N'-((3,3 -dimethyl-PAK CN (2:8, 1,2,3,5,6,7-hexa- 522 640b AD, 0.1% 483 hydrodicyclopen- 5*25 NH 3 .H 2 O ta[b,e]pyridin- 8- cm, 5 ) in yl)carbamoyl)-3- a CO 2 fluorothiophene-2-sulfonimidamide (from Ex. 519)

Number- Ex. LC-MS ro Target Structure IUPAC Name Column Eluents # [M+H]+ Final (R, R) or (S, R) or (R, S) or (S, S)-5- (1 ,2-di-CHI-40% hydroxypropan-2-yl)-RAL-MeOH:A N'-((3,3-dimethyl-PAK CN (2:8, 1,2,3,5,6, 7-hexa-523 640a AD, 0.1% 483 hydrodicyclopen- 5*25 NH 3 .H 2 O ta[b,e]pyridin-8-cm, 5) in yl)carbamoyl)-3- a CO 2 fluorothiophene-2- sulfonimidamide (from Ex. 519) (R, S) or (R, R) or (S, R) or (S, S)-N'-((2-cyclopropyl-3,7-CHIRAL dimethyl-6 ,7-di-ART 20% hydro-5H-Cellulo-EtOH 524 656d cyclopense-SB, in Hex 449 ta[b]pyridin-4-2*25 (0.1% yl)carbamoyl)-4- (2-cm, 5 of FA) hydroxypropan-2-anyl)thiophene-2-sulfonimidamide (S,S) or (S,R) or (R,S) or (R,R)-N'-(( 2-cyclopropyl-CHIRAL 3,7-dimethyl-6,7-di-ART 20%

HO hydro-5H- Cellulo- EtOH

H 525 656b N cyclopense-SB, in Hex 449

NNS ta[b]pyridin-4-2*25 (0.1% * SOO * H2N yl)carbamoyl)-4-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiophene-2-sulfonimidamide ( R, R) or (R, S) or (S, R) or (S, S)-N'-((2-cyclopropyl-3,7-CHIRAL dimethyl-6,7-di-ART 20% of

HO hydro-5H- Cellulo- EtOH

H 526 656a N cyclopense-SB, in Hex 449

N N S ta[b]pyridin-4-2*25 (0.1% * S O O * H2N yl)carbamoyl)-4-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiophene-2-sulfonimidamide

Number- Ex. LC-MS ro Target Structure IUPAC Name Column Eluents # [M+H]+ Final (S, R) or (S, S) or (R, S) or (R, R)-N'-( (2-cyclopropyl-CHIRAL 3,7-dimethyl-6,7-di-ART 20%

HO hydro-5H- Cellulo- EtOH

H 527 656c N cyclopense-SB, in Hex 449

NNS ta[b]pyridin-4-2*25 (0.1% * SOO * H2N yl)carbamoyl)-4-(2-cm, 5 of FA)hydroxypropan-2-umyl)thiophene-2-sulfonimidamide ( R, R) or (R, S) or (S, R) or (S, S)-1-(Difluoromethyl)-N'-CHI- 30% F ((3-ethyl-1,2,3, 5,6,7- RAL- NH EtOH

F N hexa-PAK IG, 528 668c N * N N in Hex 425 S hydrodicyclopen- 2.0*25

OO (0.1% H 2 N ta[b,e]pyridin-8-cm, 5* of FA)yl)carbamoyl)-1H- a pyrazol-3-sulfonimidamide (R,S) or (R,R) or (S, R) or (S, S)-1-(Difluoromethyl)-N'-CHI- 30% F ((3-ethyl-1,2,3,5,6,7-RAL-NH EtOH

F N hexa-PAK IG, 529 668b N * N N in Hex 425 S hydrodicyclopen- 2.0*25

OO (0.1% H 2 N ta[b,e]pyridin-8-cm, 5* of FA)yl)carbamoyl)-1H- a pyrazol-3-sulfonimidamide (S,S) or (S,R) or (R,S) or (R,R)-1-(Difluoromethyl)-N'-CHI- 30% of ((3-ethyl-1,2,3,5,6,7-RAL-EtOH hexa-PAK IG, 530 668a in Hex 425 hydrodicyclopen-2.0*25 (0.1% ta[b,e]pyridin-8-cm, 5 of FA) yl)carbamoyl)-1H-a pyrazol-3-sulfonimidamide

Number- Ex.

LC-MS ro Target Structure IUPAC Name Column Eluents # [M+H]+ Final (S, R) or (S, S) or (R, S) or (R, R)-1-(Difluoromethyl)-N' - CHI- 30% of ((3-ethyl-1,2,3,5,6,7-RAL-EtOH hexa-PAK IG, 531,668d in Hex 425 hydrodicyclopen- 2.0*25 (0.1% at rt [b,e]pyridin-8-cm, 5 of FA)yl)carbamoyl)-1H-uM pyrazol-3-sulfonimidamide (R,R) or (R,S) or (S,R) or (S,S )-N'-((3-ethyl-1,2,3,5,6,7-CHI- 30% hexa-RAL-EtOH hydrodicyclopen-PAK IG, in Hex 532 671d ta[b,e]pyridin- 8-467 2.0*25 (NH 3 .Meyl)carbamoyl)-3-cm, 5 OH 8 fluoro-5-(2-uM mM)hydroxypropan-2-yl)thiophene-2-sulfonimidamide (R,S) or (R, R) or (S, R) or (S, S)-N'-((3-ethyl-1,2,3,5,6,7-CHI-30% hexa-RAL-EtOH hydrodicyclopen-PAK IG, in Hex 533 671c ta[b,e]pyridin-8-467 2.0*25 (NH 3 .Meyl)carbamoyl)-3-cm, 5 OH 8 fluoro-5-(2-uM mM ) hydroxypropan-2-yl)thiophene-2-sulfonimidamide (S, R) or (S, S) or (R, S) or (R, R)-N'-((3-ethyl-CHI- 30% of 1,2,3,5,6,7-hexa-RAL-EtOH hydrodicyclopen-PAK IG, in Hex 534 671b ta[b,e]pyridin-8-467 2.0* 25 (NH 3 .Meyl)carbamoyl)-3-cm, 5 OH 8 fluoro-5-(2-uM mM)hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Number- Ex. LC-MS ro Target Structure Name IUPAC Column Eluents # [M+H]+ Final (S, S) or (S, R) or (R, S) or (R, R)-N'-( (3-ethyl-CHI-30% 1,2,3,5,6,7-hexa-RAL-EtOH hydrodicyclopent-PAK IG, in Hex 535 671a ta[b,e]pyridin-8-467 2.0 *25 (NH3.Meyl)carbamoyl)-3-cm, 5 OH 8 fluoro-5-(2-uM mM)hydroxypropan-2-yl)thiophene-2-sulfonimidamide (R,S) and (S,S) or (R, R) and (S, R)-2-(1,2-dihydroxypropan-2-yl)-

CHIRAL N'-((3-methyl-2-ART 30% (trifluoromethyl)-6,7-Cellulo-EtOH dihydro-5H- 536 605d se-SB, in Hex 480 cyclopen-2*25 (0. 1% ta[b]pyridin-4-cm, 5 of FA)yl)carbamoyl)thiazol-1M 5-sulfonimidamide (from Ex. 240; mixture of two isomers) (R,R) and (S,R) or (R,S) and (S,S)-2-(1,2-dihydroxypropan-2-yl)-N'-((3-methyl-2-CHIRAL(trifluoromethyl)-6,7-ART 30% dihydro-5H-Cellulo-EtOH 537 605b cyclopense-SB, in Hex 480 ta[b]pyridin-4-2*25 (0.1% yl)carbamoyl)thiazol-cm, 5 FA ) 5-sulfonimidamide uM (from Ex. 240; mixture of two isomers)

Number- Ex.

LC-MS ro Target Structure IUPAC Name Column Eluents No. [M+H]+ Final (R, R/S) or (S, R/S)-N- ((1,2,3,5,6,7- hexahydrodicyclopen-CHI- 30% ta[b,e]pyridin-8-RAL-EtOH yl)carbamoyl)-4-(1-PAK IG, in Hex 538 643a hydroxyethyl)-2-(2-466 0, 46*10 (0.1% hydroxypropan-2-cm, 3 of FA) yl)thiazol-5-a sulfonimidamide (from Ex. 237; mixture of two isomers) (S, R/S) or (R, R/S)-N-((1,2,3,5,6,7-hexahydrodicyclopen-CHI- 30% ta[b,e]pyridin-8-RAL-EtOHyl)carbamoyl)-4- (1-PAK IG, in Hex 539 643b hydroxyethyl)-2-(2-466 0.46*10 (0.1% hydroxypropan-2-cm, 3 of FA) yl)thiazol-5- a sulfonimamide (from from Ex. 237; mixture of two isomers) Column 2: Reg-AD, 30*250 mm, 5 µm, 20% of (R, R) or (R, S) or IPA in Hex (8 (S, R) or (S,S)-1-mM Isopropyl-N'-((3- *NH3.MeOH) for H2NO methyl-1,2,3,5,6,7-O separate two S hexa- 540 171c * NN isomers of 403 NN hydrodicyclopen- H fast coeluting N ta[b,e]pyridin-8- from Column 1 yl)carbamoyl)-1H- Chiralpak IC, pyrazol-4- 2*25 cm, 5 µm, s ulfonimimidamide 30% MeOH (0.1% DEA) in CO2

Number- Ex. LC-MS ro Target Structure IUPAC Name Column Eluents no. [M+H]+ Final Column 2: Reg-AD, 30*250 mm, 5 µm, 20% of (R, S) or (R, R ) or IPA in Hex (8(S,R) or (S,S)-1-mM Isopropyl-N'-((3-*NH3.MeOH) to H2NO methyl-1,2,3,5, 6,7- The separate two S hexa- 541 171b * NN isomers of 403 NN hydrodicyclopen- H fast coelution N ta[b,e]pyridin-8- from Column 1 yl)carbamoyl)-1H- Chiralpak IC, pyrazol-4 - 2*25 cm, 5 µm, sulfonimidamide 30% MeOH (0.1% DEA) in CO 2 Column 2: CHIRALPAK AD, (S, R) or (S, S) or 5*25 cm, 5 one, (R, S) or (R, R)-1- 50% EtOH Isopropyl-N'-((3- in CO2 to *H2 NO methyl-1,2,3,5,6,7- separate two

O S hexa-isomers of 542 171a * N N 403 N N hydrodicyclopent- slow coelution

HN ta[b,e]pyridin-8- from Column 1 yl)carbamoyl)-1H-Chiralpak IC, pyrazol-4- 2*25 cm, 5 µm, sulfonimidamide 30% MeOH (0.1% DEA) in CO2 Column 2: CHIRALPAK AD, (S, S) or (S, R) or 5*25 cm, 5 µm, (R, S) or (R, R)-1- 50% EtOH Isopropyl-N '-((3- in CO2 to *H2 NO methyl-1,2,3,5,6,7- separate two

O S hexa-isomers of 543 171d * N N 403 N N hydrodicyclopent- slow coelution

HN ta[b,e]pyridin-8- from Column 1 yl)carbamoyl)-1H-Chiralpak IC, pyrazol-4- 2*25 cm, 5 µm, sulfonimidamide 30% MeOH (0.1% DEA) in CO2

Example 544 (Compound 734) N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(1 ,2,3-Trihydroxypropan-2-yl)thiazol-5-sulfonimidamide (Scheme VIII) Step 1: N'-(tert-butyldimethylsilyl)-N-((3,3-dimethyl-1,2,3, 5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazol-5- sulfonimidamide

[002622] To a stirred solution of N'-(tert-butyldimethylsilyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazol-5-sulfonimidamide (50 mg, 0 .12 mmol) in THF (10 ml) in a 25 ml round bottom flask under nitrogen was added NaH (60% by weight dispersion in mineral oil, 24 mg, 0.61 mmol) at 0 °C. The resulting solution was stirred for 10 min at 0 °C. To the solution was added 2,2,2-trichloroethyl (3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (46 mg, 0.12 mmol) in portions at 0°C. The resulting mixture was stirred for 2 h at 35 °C. The reaction was quenched by the addition of 10 ml of water/ice at 0°C and extracted with 3x15 ml of EtOAc. The combined organic layers were washed with brine (3x15 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC (PE/EtOAc = 3:1). This resulted in 60 mg (77%) of the title compound as a white-white solid.

dirty. MS-ESI: 636 (M+1). Step 2: N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]-pyridin-8-yl)carbamoyl)-2-(1,2 ,3-trihydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002623] To a stirred solution of N'-(tert-butyldimethylsilyl)-N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8 -yl)carbamoyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazol-5-sulfonimidamide (60 mg, 0.094 mmol) in THF (5 ml) in a flask 25 ml round bottom was added HCl in 1,4-dioxane (4M, 1.25 ml) dropwise at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep HPLC. with the following conditions: XBridge Prep OBD C18 column, 30×150 mm, 5 µm; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 5% B to 25% B for 7 min; UV 254/210 nm; Rt: 4.95 min. This resulted in 17.1 mg (38%) of Example 544 as a white solid. MS-ESI: 482 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 8.22 (s, 1H), 3.91-3.83 (m, 4H), 2.98 (t, J = 7.6 Hz, 2H), 2 .87-2.77 (m, 4H), 2.16-2.09 (m, 2H), 2.00-1.96 (m, 2H), 1.40 (s, 6H). Table 40. The examples in the following table were prepared using conditions similar to those described in Example 9 and Scheme 2 from appropriate starting materials. Target Exemplary Final Mass Structure Exact IUPAC Name No Number [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e ]pyridin-8- 545 736 yl)carbamoyl)-2-((R)-2-hydroxy-1-(2-methoxyethoxy)propan-2-yl)thiazol-5-sulfonimidamide

Target Exemplary Final Mass Structure Exact IUPAC Name No Number [M+H]+ 3-(N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[ b,e]pyridin-8-546 735 478 yl)carbamoyl)sulfamidimid oil)-N-methylbenzenesulfonamide 4-ethyl-N'-(((R)-3-methyl-1,2,3,5,6 ,7-hexa-HN N hydrodicyclopen- 547 721c 405 N ta[b,e]pyridin-8-(R)SSO yl)carbamoyl)thiophene-2-

NH 2 abs sulfonimidamide Table 41. The examples in the following table were prepared using conditions similar to those described in Example 236 and Scheme II from appropriate starting materials. Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 5-Ethyl-3-fluoro-N'-(((R)-3-methyl-1,2,3,5,6,7-hexa-

F

HN N hydrodicyclopen-548 423 N ta[b,e]pyridin-8-(R)

S S O O yl)carbamoyl)thiophene-2-NH2 abs sulfonimidamide

Table 42. The examples in the following table were prepared using conditions similar to those described in Example 252 and Scheme V from appropriate starting materials. Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-(1,1-Difluoroethyl)-N'-(R) (((R)-3-methyl-1,2,3,5,6 ,7- abs hexa- 549 F HN N hydrodicyclopen- 425

N N N S O ta[b,e]pyridin-8-

FOH 2N yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 4-Chloro-1-ethyl-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta [b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide Table 43. The examples in the following table were obtained from chiral HPLC resolutions of racemic examples. The chiral column and eluents are listed in the table. As a convention, the fastest-eluting enantiomer is always listed first in the table, followed by the slower-eluting enantiomer of the pair. The symbol * in a chiral center denotes that the chiral center has been separated, and the absolute stereochemistry at that chiral center has not been determined. The stereochemistry assigned in compound names is provisional.

Number Ex. Eluen- LC-MS Target Structure Name IUPAC Column No. tes [M+H]+ Final (R) or (S)-1-(1,1-Difluoroethyl)-N'-CHI- 50% ((( R)-3-methyl-RAL- from IPA 1,2,3,5,6,7-hexa-PAK in 553 723b hydrodicyclopen-IE, 425 Hex ta[b,e]pyridin-8-2*25 (0 .1% yl)carbamoyl)-1H-cm, 5 of FA) pyrazol-3- a sulphonimidamide (S) or (R)-1-(1,1-Difluoroethyl)-N'-CHI- 50% ((( R)-3-methyl-RAL- from IPA 1,2,3,5,6,7-hexa-PAK in 554 723a hydrodicyclopen-IE, 425 Hex ta[b,e]pyridin-8-2*25 (0 .1% yl)carbamoyl)-1H-cm, 5% FA) pyrazol-3- a sulfonimidamide (R) or (S)-4-ethyl-30% CHI-N'-(((R)-3-methyl - from RAL-1,2,3,5,6,7-hexa-EtOH

PAK hydrodicyclopen-em 555 721b IC, 405 ta[b,e]pyridin-8-Hex 2*25 yl)carbamoyl)thiophen (NH 3 .M cm, 5 no-2-eOH 8 a mM sulfonimamide) (S) or ( R)-4-ethyl-30% CHI-N'-(((R)-3-methyl- from RAL-1,2,3,5,6,7-hexa-EtOH

PAK hydrodicyclopen-em 556 721a IC, 405 ta[b,e]pyridin-8-Hex 2*25 yl)carbamoyl)thiophen (NH 3 .M cm, 5 n-2-eOH 8 mM sulfonimidamide)

eg number

Eluent- LC-MS Target Structure IUPAC Name Column No. [M+H]+ Final (S) or (R)-5-ethyl-CHI- 30% 3-fluoro-N'-(((R)-RAL from 3-Methyl-ART EtOH 1,2,3,5,6,7-hexa-Cellulo- on 557,720b hydrodicyclopense-SB, Hex ta[b,e]pyridin-8-2*25 (NH3.M yl)carbamoyl)thiophen cm, 5 eOH 8 no-2-one mM)sulfonimidamide (R) or (S)-5-ethyl-CHI- 30% 3-fluoro-N'-(((R)-RAL of 3 -methyl-ART EtOH 1,2,3,5,6,7-hexa-Cellulo- at 558,720a hydrodicyclopense-SB, Hex ta[b,e]pyridin-8-2*25 (NH3.M yl )carbamoyl)thiophen in, 5 eOH 8 no-2-one mM)sulfonimidamide (R) or (S)-4-chloro-1-ethyl-N'-((3-CHI- 30% methyl-2-RAL- of (trifluoromethyl)-PAK EtOH 6,7-dihydro-5H- 559 729b IE, in 451 cyclopen- 2*25 Hexta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)- 1H- one of FA) pyrazol-3-sulfonimidamide (S) or (R)-4-chloro-1-ethyl-N'-((3-CHI- 30% methyl-2-RAL- from (trifluoromethyl)-PAK EtOH 6,7-dihydro-5H- 560 729a IE, in 451 cyclopent-2*25 Hex ta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)-1H-one of FA) pyrazol-3-sulfonimidamide

Example 561 1-(Difluoromethyl)-4-fluoro-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)- 1H-pyrazol-3-sulfonimidamide (Scheme IX) Examples 562 and 563 (R)- and (S)--1-(difluoromethyl)-4-fluoro-N'-((3-methyl-2-(trifluoromethyl) )-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide Step 1: N-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4 -fluoro-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

[002624] To a stirred solution of N'-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-1H-pyrazol-3-sulfonimidamide (150 mg, 0.46 mmol) in THF (10 ml) in To a 50 ml round bottom flask under nitrogen was added NaH (60 wt% mineral oil dispersion, 54.8 mg, 1.37 mmol) at 0 °C in an ice/water bath. The resulting solution was stirred for 10 min at RT. Then, 2,2,2-Trichloroethyl (3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (179 mg, 0.46 mmol ) was added to the stirred solution. The resulting solution was stirred for 20 h at RT. The reaction was then stopped with the addition of 1.0 ml of MeOH. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 250 mg (96%) of the title compound as a pale yellow oil. MS-ESI: 571(M+1). Step 2: 1-(Difluoromethyl)-4-fluoro-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl) -1H-pyrazol-3-sulfonimidamide

[002625] To a stirred solution of N-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H - cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (250 mg, 0.45 mmol) in THF (5.0 ml) in a 50 ml round bottom flask was added KF (131 mg, 2.25 mmol) at RT. The resulting solution was stirred for 1 h at RT. Solids were removed by filtration. The resulting mixture was concentrated. The crude product was purified by prep HPLC. using the following conditions: XBridge Prep C18 OBD column, 19×150 mm, 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 8% B to 28% B for 7 min; UV 210/254 nm; Rt: 5.32 min. This resulted in 155 mg (74%) of Example 561 as an off-white solid. MS-ESI: 457 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.04 (sl, 2H), 7.86 (t , J = 58.4 Hz, 1H), 2.94-2.88 (m, 2H), 2.80-2.74 (m, 2H), 2.20 (s, 3H), 2.07- 1.98 (m, 2H).

Step 3: Chiral Resolution

[002626] Example 561 (150 mg) was separated by prep-chiral HPLC using the following conditions: CHIRALPAK IG, 20*250 cm, 5 µm; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: EtOH; Flow rate: 20 ml/min; Gradient: 20% B; 220/254 nm; Rt1: 6.505 min (Example 562), Rt2: 8.721 min (Example 563); This resulted in 37.0 mg of Example 562 followed by 42.4 mg of Example 563, both as an off-white solid.

[002627] Example 562: MS-ESI: 457 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.11 (sl, 2H), 7.86 (t , J = 58.4 Hz, 1H), 2.94-2.88 (m, 2H), 2.78-2.67 (m, 2H), 2.20 (s, 3H), 2.09- 1.97 (m, 2H).

[002628] Example 563: MS-ESI: 457 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.65 (d, J = 4.4 Hz, 1H), 8.11 (sl, 2H), 7.86 (t , J = 58.4 Hz, 1H), 2.94-2.87 (m, 2H), 2.81-2.71 (m, 2H), 2.20 (s, 3H), 2.09- 1.96 (m, 2H). Table 49. The examples in the following table were prepared using conditions similar to those described in Example 561 and Scheme IX from appropriate starting materials. Exemplary Mass Structure Exact IUPAC Name No [M+H]+ (6R)-6-methoxy-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[ b]pyridin-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4- 565,445 yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide 4-(2-hydroxypropan-2-yl)-N'-(( 2-methyl-3-(trifluoromethyl)-6,7-di-hydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide 4-(2-hydroxypropan-2-yl) - N'-((2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide 1-(Difluoromethyl)-4-fluoro - N'-(((R)-3-methyl-1,2,3,5,6,7-hexa-hydrodicyclopent-429 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazole - 3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-(Difluoromethyl)-4-fluoro-N'-((1',5',6',7'-tetrahydro-2'H- spiro[cyclopropane-569 1,3'-441 dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((2,3-dicyclopropyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide N'-((2,3- dicyclopropyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-(difluoromethyl)-1H-pyrazol-3-sulfonimidamide 1-(Difluoromethyl)-N'-( (3-ethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-4-fluoro-1H-pyrazol-3-sulfonimidamide Example 573 ( R) H2N (R) OH

s No N N N N

FO (R)-1-(fluoromethyl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamoyl)-1H-pyrazole-3-

sulfonimidamide (Scheme X) Step 1: tert-butyl((R)-(1-(fluoromethyl)-1H-pyrazol-3-yl)(3-((R)-3-methyl-1,2,3,5 ,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)ureido)(oxo)-λ6-sulfaneylidene)carbamate

[002629] To a stirred solution of tert-butyl (S)-(amino(1-(fluoromethyl)-1H-pyrazol-3-yl)(oxo)-λ6-sulfaneylidene)carbamate (10 mg, 0.036 mmol) in THF (1.0 ml) in an 8 ml sealed tube was added K2CO3 (24.8 mg, 0.18 mmol) and (R)-(3-methyl-1,2,3,5,6, 2,2,2-Trichloroethyl 7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (13 mg, 0.036 mmol). The resulting solution was stirred for 2 h at 80 °C. The reaction mixture was cooled to RT. The resulting solution was diluted with 20 ml of EtOAc. The solids were filtered off, the filtrate was concentrated under reduced pressure. This resulted in 11 mg (crude product) of the title compound as a white solid. MS-ESI: 493 (M+1). Step 2: (R)-1-(fluoromethyl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

[002630] To a stirred solution of ((R)-(1-(fluoromethyl)-1H-pyrazol-3-yl)(3-((R)-3-methyl-1,2,3,5,6, tert-Butyl 7-hexahydrodicyclopenta[b,e]pyridin-8-yl)ureido)(oxo)-λ6-sulfaneylidene)carbamate (10mg) in DCM (10ml) in a sealed 20ml tube was added BF3.Et2O (47% by weight, 0.050 ml, 0.40 mmol) dripped at 0°C. The resulting solution was stirred for 90 min at RT. The resulting solution was quenched with 2.0 ml of MeOH. The resulting mixture was concentrated. The crude product was purified by prep HPLC. using the following conditions: XBridge Prep OBD C18 column, 30*150 mm, 5 um; mobile phase, water (10 mM NH4HCO3 + 0.1% NH3.H2O) and ACN (3% to

30% for 7 min); UV 254/220 nm; Rt: 6.13 min.

This resulted in 0.80 mg (5.7% over 2 steps) of Example 573 as a white solid.

MS-ESI: 393 (M+1). Table 50. The examples in the following table were prepared using conditions similar to those described in Example 573 and Scheme X from appropriate starting materials.

The structures of Examples 575 and 576 were assigned based on their proton NMR compared to similar literature compounds (Journal of Organic Chemistry. 2013, 78(11), 5349 to 5356). Exemplary Mass Structure Exact IUPAC Name No [M+H]+ Mixture of (R)-N'-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[ b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide and 574,478 (R)-N'-((3,6-dimethyl-2-(trifluoromethyl)) -6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (R)-N'-((3) ,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5 -sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ (R)-N'-((3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H- 576 cyclopenta[b] ]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Example 577 (R)-N'-((3-cyclopropyl-2-(trifluoromethyl)-6, 7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (Scheme XI) Step 1: tert-butyl(S) -(N-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl) thiazol-5-sulfonimidoyl)carbamate

[002631] To a stirred solution of tert-butyl (S)-(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0 .28 mmol) in THF (10 ml) in a sealed 20 ml tube was added K2CO3 (193 mg, 1.4 mmol) and (3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro 2,2,2-Trichloroethyl -5H-cyclopenta[b]pyridine-4-yl)carbamate (117 mg, 0.28 mmol) at RT. The resulting solution was stirred for 2 h at 80 °C. The reaction mixture was cooled to RT. The resulting solution was diluted

50 ml of EtOAc. Solids were removed by filtration. The filtrate was concentrated. This resulted in 100 g (crude product) of the title compound as a white solid. MS-ESI: 590 (M+1). Step 2: (R)-N'-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazol-5-sulfonimidamide

[002632] A solution of (S)-(N-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2- tert-Butyl (2-hydroxypropan-2-yl)thiazol-5-sulfonimidoyl)carbamate (100mg, 0.17mmol) in 4M HCl/dioxane (4ml) in a 50ml round bottom flask was stirred for 30 min at RT. The resulting mixture was concentrated in vacuo. The crude product was purified by prep HPLC. using the following conditions: XBridge Prep C18 OBD column, 19×150 mm, 5 um; Mobile Phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 7% B to 20% B for 10 min; UV 210/254 nm; Rt1: 11.03 min. This resulted in 30 mg (22% over 2 steps) of Example 577 as a white solid. MS-ESI: 490 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.09 (s, 1H), 7.92 (sl, 2H), 6.28 (s, 1H), 2.94 -2.87 (m, 2H), 2.84-2.79 (m, 2H), 2.07-1.98 (m, 2H), 1.83-1.78 (m, 1H), 1 .50 (s, 6H), 0.93-0.80 (m, 2H), 0.44-0.30 (m, 2H). Table 51. The examples in the following table were prepared using conditions similar to those described in Example 577 and Scheme XI from appropriate starting materials.

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ (R)-N'-((3-cyclopropyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-578 cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide (R)-N'-((2-(1-fluorocyclopropyl)-3-methyl - 6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Example 580

(6R)-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-6-(methylamino)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (Scheme XII)

Step 1: tert-butylmethyl((6R)-3-(N'-((5-methyl-6-(trifluoromethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamidimidoyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

[002633] To a stirred solution of ((6R)-3-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazol[5,1-b][1,3] tert-Butyl oxazin-6-yl)(methyl)carbamate (100 mg, 0.22 mmol) in THF (5.0 mL) in a 50 mL round bottom flask under nitrogen was added NaH (60% by weight of dispersion in mineral oil, 18 mg, 0.44 mmol) at 0 °C in an ice/water bath, followed by 2,2,2-trichloroethyl(5-methyl-6-(trifluoromethyl)-2, 3-dihydro-1H-inden-4-yl)carbamate (88 mg, 0.22 mmol) in portions at 0°C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by adding 5.0 ml of water. The resulting solution was extracted with 3x30 ml of EtOAc, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 100 mg (crude product) of the title compound as a white solid. MS-ESI: 573 (M+1). Step 2: (6R)-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-6-(methylamino) -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

[002634] To a stirred solution of tert-butylmethyl((6R)-3-(N'-((5-methyl-6-(trifluoromethyl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazol[5,1-b][1,3]oxazin-6-yl)carbamate (80 mg, 0.14 mmol) in DCM (3 ml) to a 25 ml round bottom flask was added BF3.Et2O (47% by weight, 0.05 ml, 0.40 mmol) by dripping with stirring at 0 °C in an ice/water bath. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by adding 1.0 ml of water. The resulting solution was extracted with 3x10 ml of EtOAc and dried over anhydrous sodium sulfate. Solids were removed by filtration. The resulting mixture was concentrated in vacuo. The crude product was purified by prep HPLC. using the following conditions: XSelect CSH Prep C18 OBD column, 5 µm, 19*150 mm; Mobile Phase A: water (10 mM NH4HCO3),

Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 16% B to 31% B over 7 min; 210/254 nm; Rt1: 6.05 min. This resulted in 50 mg (48%, over two steps) of Example 580 as a white solid. MS-ESI: 474 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.21 (s, 1H), 7.55 (s, 1H), 7.33 (sl, 2H), 4.40 -4.19 (m, 3H), 3.99-3.90 (m, 1H), 3.20-3.14 (m, 1H), 2.92 (t, J = 7.6 Hz, 2H ), 2.84 (t, J = 7.6 Hz, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 2.13-1.99 (m, 2H). Example 581 (R)-N'-((3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2 -yl)thiazol-5-sulfonimidamide (Scheme XIII)

[002635] Step 1: (R)-((3-(3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)ureido)(2-(2) tert-butyl -hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfanoylidene)carbamate

[002636] To a stirred solution of tert-butyl (S)-(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfanoylidene)carbamate (71 mg, 0 .22 mmol) in MeCN (10 mL) in a 25 mL round bottom flask was added DBU (100 mg, 0.66 mmol) and (3-cyclopropyl-2-methyl-6,7-dihydro- 2,2,2-Trichloroethyl 5H-cyclopenta[b]pyridin-4-yl)carbamate (80 mg, 0.22 mmol). The resulting solution was stirred for 6 h at 35 °C in an oil bath. The reaction was then stopped with the addition of 6.0 ml of water. The resulting solution was extracted with 5x20 ml of EtOAc, and the organic layers were combined and concentrated.

This resulted in 160 mg (crude product) of the title compound as a brown solid. MS-ESI: 536 (M+1). Step 2: (R)-N'-((3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan- 2-yl)thiazol-5-sulfonimidamide

[002637] To a stirred solution of (R)-((3-(3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)ureido)(2- tert-Butyl (2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.22 mmol) in dioxane (15 mL) was added conc. (12M, 0.10 ml, 1.2 mmol) by dripping at RT. The resulting solution was stirred for 2 h at RT. The pH of the mixture was adjusted to 7 with saturated NaHCO3 (aq.), then extracted with 5x20 ml of EtOAc, and the organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep HPLC. using the following conditions: XBridge Prep OBD C18 column, 30*150 mm* 5 um; mobile phase, water (10 mM NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (5% Phase B at 28% for 7 min); UV 210/254 nm; Rt1: 6.05 min. This resulted in 45 mg (46% over two steps) of Example 581 as a white solid. MS-ESI: 436 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.07 (s, 1H), 7.86 (sl, 2H), 6.28 (s, 1H), 2.81 -2.64 (m, 4H), 2.46 (s, 3H), 1.97-1.90 (m, 2H), 1.63-1.55 (m, 1H), 1.50 (s , 6H), 0.88-0.77 (m, 2H), 0.32-0.25 (m, 2H). Example 582 (R)-4-(1-hydroxyethyl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8 -yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme XIV)

Step 1: (R)-4-(1-hydroxyethyl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2-sulfonimidamide

[002638] To a stirred solution of (R)-4-acetyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin -8-yl)carbamoyl)thiophene-2-sulfonimidamide (200 mg, 0.48 mmol) in MeOH (20 mL) in a 50 mL round bottom flask under nitrogen was added NaBH4 (54 mg, 1.43 mmol). ) in portions at 0 °C in an ice/water bath. The resulting solution was stirred overnight at RT. The reaction was then quenched with the addition of 10 ml of 1M HCl. The resulting solution was extracted with 2x50 ml of EtOAc and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep HPLC. using the following conditions: XBridge Prep C18 OBD speaker, 19*150 mm, 5 um; mobile phase, water (10 mM NH4HCO3 + 0.1% NH3.H2O) and ACN (5% Phase B at 25% for 7 min); UV 210/254 nm, Rt: 6.63 min. This resulted in 160 mg (80%) of Example 582 as a white solid. MS-ESI: 421 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.71 (sl, 2H), 7.60 (s, 2H), 5.33 (d, J = 4.8 Hz , 1H), 4.79-4.68 (m, 1H), 3.05-2.97 (m, 1H), 2.85-2.60 (m, 6H), 2.29-2.21 (m, 1H), 2.01-1.90 (m, 2H), 1.54-1.43 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H), 1, 20 (d, J = 7.2 Hz, 3H). Table 52 The examples in the following table were prepared using conditions similar to those described in Example 582 and Scheme XIV from Example 666.

Mass Example Structure Exact IUPAC Name at [M+H]+ (S)-4-(1-hydroxyethyl)-N'- (((R)-3-methyl-1,2,3,5,6,7- hexa-583 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide Example 584 2-((S)-1,14-dihydroxy-3,6,9,12- tetraoxapentadecan-14-yl)-N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide (Scheme XV) Step 1: N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2- ((S)-16-hydroxy-1-phenyl-2,5,8,11,14-pentaoxaheptadecan-16-yl)thiazol-5-sulfonimidamide

[002639] To a stirred solution of N'-(tert-butyldimethylsilyl)-2-((S)-16-

hydroxy-1-phenyl-2,5,8,11,14-pentaoxahepta-decan-16-yl)thiazol-5-sulfonimidamide (100 mg, 0.16 mmol) in THF (5.0 mL) in a vial of 50 ml round bottom under nitrogen, 2,2 (3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate, 2-Trichloroethyl (60 mg, 0.16 mmol) and NaH (60% by weight dispersion in mineral oil, 13 mg, 0.32 mmol) at 0 °C in an ice/water bath. The resulting solution was stirred for 3 h at RT. The reaction was then stopped with the addition of 5.0 ml of water. The resulting solution was extracted with 3x30 ml of EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate. The solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 100 mg (85%) of the title compound as a white solid. MS-ESI: 732 (M+1). Step 2: 2-((S)-1,14-dihydroxy-3,6,9,12-tetraoxapentadecan-14-yl)-N-((3,3-dimethyl-1,2,3,5) ,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide

[002640] To a stirred solution of N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-( (S)-16-hydroxy-1-phenyl-2,5,8,11,14-pentaoxaheptadecan-16-yl)thiazol-5-sulfonimidamide (80 mg, 0.11 mmol) in DCM (15 ml), was BCl3 in DCM (1 M, 0.46 ml, 0.46 mmol) is added by dropping it at 0 °C in an ice/water bath under nitrogen. The resulting mixture was stirred for 5 h at 0 °C. The reaction was quenched with water/ice (10 ml) at 0°C. The resulting mixture was extracted with DCM (3 x 30 ml). The combined organic layers were washed with brine (10 ml) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by prep. using the following conditions: XSelect CSH Prep C18 OBD column, 5 µm, 19*150 mm; Mobile Phase A: water (10 mM NH4HCO3+ 0.1%

NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 ml/min; Gradient: 18% B to 28% B for 7 min; UV 210/254 nm; Rt1: 6.20 min. This resulted in 18.7 mg (27%) of Example 584 as a white solid. MS-ESI: 642 (M+1). 1H NMR (300 MHz, MeOH-d4) δ 8.19 (s, 1H), 3.90-3.48 (m, 18H), 3.01-2.91 (m, 2H), 2.89- 2.72 (m, 4H), 2.20-2.01 (m, 2H), 2.01-1.80 (m, 2H), 1.57 (s, 3H), 1.28 (s, 6H). Example 585 5-(hydroxymethyl)-1-isopropyl-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)- 1H-Pyrazol-3-sulfonimidamide (Scheme XVI) Step 1: N-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-N'-((3-methyl) -2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

[002641] To a stirred solution of N'-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide (300 mg, 0.67 mmol ) in THF (5.0 ml) under nitrogen was added NaH (60% by weight, dispersion in mineral oil, 80.4 mg, 2.01 mmol) in portions at 0°C. The reaction mixture was stirred for 20 min at 0 °C. To the above mixture was added 2,2,2-trichloroethyl (3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (263 mg, 0 .67 mmol) in THF (3.0 ml) by dropping at 0°C. The resulting mixture was stirred for 2 h at RT. The reaction was quenched with water/ice (10 ml) at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparatory TLC with PE/EtOAc (4:1). This resulted in 375 mg (81%) of the title compound as a yellow solid. MS-ESI: 689 (M+1). Step 2: 5-(Hydroxymethyl)-1-isopropyl-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl) -1H-pyrazol-3-sulfonimidamide

[002642] To a stirred solution of N-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-N'-((3-methyl-2-(trifluoromethyl)-6 ,7-Dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (370 mg, 0.54 mmol) in THF (5.0 mL) was added tri- triethylamine hydrofluoride (0.33 ml, 2.03 mmol, 4.50 equiv.) in portions at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was concentrated in vacuo. The residue was purified by Prep HPLC. with the use of the following conditions. XBridge Prep OBD C18 column, 30×150 mm, 5 µm; Mobile Phase A: water (10 mM NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 5% B to 35% B for 7 min; UV 254/210 nm; Rt1: 6.22 min. This resulted in 100 mg (40%) of Example 585 as a white solid. MS-ESI: 461 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.41 (sl, 2H), 6.55 (s, 1H), 5.46 (t, J = 5.4 Hz , 1H), 4.75-4.61 (m, 1H), 4.55 (d, J = 5.6 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2 .80 (t, J = 7.2 Hz, 2H), 2.21 (s, 3H), 2.08-1.94 (m, 2H), 1.39 (t, J = 6.6 Hz, 6H). Table 53 The examples in the following table were prepared using conditions similar to those described in Example 544 and Scheme VIII from appropriate starting materials.

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin- 8-586 yl)carbamoyl)-4-512 (hydroxymethyl)-2-(1,2,3-trihydroxypropan-2-yl)thiazol-5-sulfonimidamide 4-(hydroxymethyl)-N'-((2- methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(1,2,3-trihydroxypropan-2-yl) thiazol-5-sulfonimidamide 1-ethyl-5-(hydroxymethyl)-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-Ethyl-5-(hydroxymethyl)-N'-((1',5',6',7'-tetrahydro-2'H- spiro[cyclopropane-1,3'-589,431 dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-ethyl-5-(hydroxymethyl)-N'- (((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopen- 590 419 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1-ethyl-5- (hydroxymethyl)-1H-pyrazol-3-sulfonimidamide Table 54 The examples in the following table were prepared using conditions similar to those described in Example 250 and Scheme III from appropriate starting materials.

Example- Exa Mass- Structure IUPAC Name by Note [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e] pyridin-8-592yl)carbamoyl)-4-507((dimethylamino)methyl)-2-(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide Table 55. The examples in the following table were prepared using conditions similar to those described in Example 49 and Scheme 3 from appropriate starting materials.

Example- Exa Mass- Structure IUPAC Name by Note [M+H]+ 2-(2-hydroxypropan-2-yl)-N'-((3-oxo-1,2,3,5,6,7- hexa-593hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide Table 56. The examples in the following table were prepared using conditions similar to those described in Example 236 and Scheme. - ma II from appropriate starting materials.

Example Exa Mass- Structure IUPAC Name by Note [M+H]+ N'-((3-ethyl-2-(2,2,2-trifluoroethyl)-6,7-di-CF3 F H2 NO hydro- 5H-

S cyclopenta[b]pyridin-

N N 594 4-yl)carbamoyl)-3-509

S O N fluoro-5-(2-H hydroxypropan-2-

OH yl)thiophene-2-sulfonimidamide 5-(hydroxymethyl)-1-isopropyl-N'-((1',5',6',7'-tetrahydro-2'H-spiro[cyclopropane-5951, 3'-445 dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 5-(hydroxymethyl)-1-isopropyl-N'-(((R)-3 - methyl-1,2,3,5,6,7-hexa-hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Example Exa Mass- Structure IUPAC Name by Note [M+H]+ 1-ethyl-4-fluoro-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H- 597,435 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 2-(1,2-dihydroxypropan-2-yl)-N'-((3,3-dimethyl-1) ,2,3,5,6,7-hexa-598 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(hydroxymethyl)thiazol-5-sulfonimidamide 2-((S)-1 ,2-dihydroxypropan-2-yl)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-hydrodicyclopenta[b,e]pyridin-8 -yl)carbamoyl)-4-(hydroxymethyl)thiazol-5-sulfonimidamide 2-((R)-1,2-dihydroxypropan-2-yl)-N'-((3,3-dimethyl-1,2) ,3,5,6,7-hexa-600 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(hydroxymethyl)thiazol-5-sulfonimidamide

Example- Exa Mass- Structure IUPAC Name by Note [M+H]+ (6R)-6-hydroxy-N'- ((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-601 461 4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide 1-ethyl-4-fluoro -N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopent-602 407 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazole -3-sulfonimidamide (6R)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl) -6- hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide 2-(1,3-dihydroxy-2-methylpropan-2 -yl)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa-hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-5 - sulfonimidamide

Example- Exa Mass- Structure IUPAC Name by Note [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-2-(1-hydroxy-2-methylpropan-2-yl)thiazol-5-sulfonimidamide 2-(1,2-dihydroxypropan-2-yl)-N'- ((3-methyl-2-(1-methylcyclopropyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)thiazol-5-sulfonimidamide 5-((R)- 1,2-dihydroxypropan-2-yl)-3-fluoro-N'-((1',5',6',7'-tetrahydro-2'H-spiro[cyclopropane-1, 3'-dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)thiophene-2-sulfonimidamide

Example Exa Mass Structure IUPAC Name by Note [M+H]+ 5-((S)-1,2-dihydroxypropan-2-yl)-3-fluoro-N'- ((1',5 ',6',7'-tetrahydro-2'H-608,481 spiro[cyclopropane-1,3'-dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)thiophene-2-sulfonimidamide Table 57. The examples in the following table were prepared using conditions similar to those described in Example 252 and Scheme V from appropriate starting materials.

Example Exa Mass- Structure IUPAC Name by Note [M+H]+ N'-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-609,489 4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide N'-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-CF3 cyclopenta [b]pyridin-

F 610 HN N 4-yl)carbamoyl)-3-507

No

S fluoro-5-(2-

OH S O O hydroxypropan-2-H2N yl)thiophene-2-sulfonimidamide

Example Exa-Mass Structure IUPAC Name by Note [M+H]+ N'-((2-(1-fluorocyclopropyl)-3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin - 453 4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 3-Fluoro-N'-((2-(1-fluorocyclopropyl)-3-methyl-6,7- dihydro-5H-cyclopenta-612[b]pyridin-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 4-(3-(((tert-butyldimethylsilyl)) -amino)(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-16-sulfa-noylidene)ureido)-3-methyl-6,7-dihydro- Ethyl 5H-cyclopenta-[b]pyridine-2-carboxylate N'-((2-(difluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2 -(2-hydroxypropan-2-yl)thiazol-5-sulfonimidamide

Example Exa-Mass Structure IUPAC name by note [M+H]+ N'-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-615,483 4-yl)carbamoyl)-1-(difluoromethyl)-4-fluoro-1H-pyrazol-3-sulfonimidamide 1-ethyl-4-fluoro-N'-(((S)-3-methyl-1,2,3 ,5,6,7-hexahydrodicyclopent-616 407 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-(Difluoromethyl)-4-fluoro-N'-(( 3-methyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N' -((2,3-dicyclopropyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide

Example- Exa Mass- Structure IUPAC Name by Note [M+H]+ 1-ethyl-4-fluoro-N'-((3-methyl-2-(2,2,2-trifluoroethyl)-6,7- dihydro-5H- 619,449 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-(Difluoromethyl)-4-fluoro-N'-((2-methyl-3-phenyl) -6,7-dihydro-5H-cyclopenta[b]pyridin-465 4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-(Difluoromethyl)-N'-((3,3-dimethyl- 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-fluoro-1H-pyrazol-3-sulfonimidamide

Table 58 The examples in the following table were prepared using conditions similar to those described in Example 9 and Scheme 2 from appropriate starting materials.

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-(2-hydroxyethyl)-N'- ((1',5',6',7'-tetrahydro-2'H-spiro[ cyclopropane-622 1,3'-dicyclopenta-417[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 4-((S)-1,2-dihydroxypropan-2 -yl)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclo-penta[b,e]pyridin-8-yl)carbamoyl)thiophene-2 - 4-((R)-1,2-dihydroxypropan-2-yl)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclo-sulfonimidamide) 465 penta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide 5-((R)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N'- ((1,1-dimethyl-1,2,3,5,6,7-625,599 hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]-pyridin-8 -yl)carbamoyl)-1- 626 449 (2-hydroxyethyl)-5-(hydroxymethyl)-1H-pyrazol-3-sulfonimidamide 4-Acetyl-N'-(((R)-3-methyl-1, 2,3,5,6,7-hexahydrodicyclopent-ta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide 1-ethyl-4-fluoro-N'-((1' ,5',6',7'-tetrahydro-2'H-spiro[cyclopropane-1,3'-dicyclopenta-419[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazole - 3-sulfonimidamide 2-ethyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopent-629 406 ta[b,e]pyridin-8-yl )carbamoyl)thiazole-5-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin- 8- 630 444 yl)carbamoyl)-6-(2-hydroxypropan-2-yl)pyridin-2-sulfonimidamide 3-ethyl-N'-(((R)-3-methyl-1,2,3,5, 6,7-hexahydrodicyclopen- 631 404 ta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide N'-((2,3-dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-632415yl)carbamoyl)-1-ethyl-1H-pyrazol-3-sulfonimidamide 1-Methyl-N'-((3-methyl-2-(trifluoromethyl)-6,7-di - hydro-5H- 633 403 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-ethyl-N'-((3-methyl-2-(trifluoromethyl)-6,7- dihydro-5H- 634 417 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ N'-((3-hydroxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8 - 438 yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazol-2-sulfonimidamide 4-(3-(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)( oxo)-16-sulfanoylidene)ureido)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylic N'-((2-cyclopropyl-3-methyl-6, 7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide N'-((3,3-dimethyl-1 ,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide 1-cyclopropyl -4-fluoro-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole - 3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-cyclopropyl-4-fluoro-N'- (((R)-3-methyl-1,2,3,5,6,7-hexa- hydrodicyclo-855 419 penta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((2,3-bis(trifluoromethyl)-6,7-dihydro-5H- cyclopenta-856 [b]pyridin-4-yl)carbamoyl)-489 1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide 1-cyclopropyl-4-fluoro-N'-((1',5', 6',7'-Tetrahydro-2'H-spiro[cyclopropane-1,3'-dicyclopenta-431[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-cyclopropyl-4-fluoro-N'-F ((1,2,3,5,6,7-hexa-

N H

NN hydrodicyclopen-858 NN 405 Sta[b,e]pyridin-8-H2N OOyl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-cyclopropyl-N'-((3-methyl-2-(trifluoromethyl)- 6,7-dihydro-5H- 859,429 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-cyclopropyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopen-860,401 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-cyclopropyl-N'-((1',5',6',7'-tetrahydro-2'H -spiro[cyclopropane-1,3'-861,413 dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-cyclopropyl-N'-((1,2,3 ,5,6,7-hexahydrodicyclopent-862 387 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide Table 59 The examples in the following table were obtained from chiral resolutions HPLC of examples of racemic and diastereomeric mixtures described above.

The chiral column and eluents are listed in the table.

As a convention, the fastest-eluting enantiomer is always listed first in the table, followed by the slower-eluting enantiomer of the pair.

The symbol * in a chiral center denotes that the chiral center has been separated, and the absolute stereochemistry at that chiral center has not been determined.

The stereochemistry assigned in compound names is provisional.

Some carbon stereocenters were arbitrarily assigned for recording purposes, such as the alcohol centers for Examples 661~664.

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-N'-((3-ethyl-2-CHI-(2,2,2-trifluoroethyl)-6, 7-di-20% RAL-hydro-5H-cyclopenta-EtOH PAK IA, 639 [b]pyridin-4-yl)carbamoyl)- in Hex 509 4.6*50 3-fluoro-5-(2-hydroxypro - (0.1% mm; 3-pan-2-yl)thiophene-2- from FA) a sulfonimidamide (S) or (R)-N'-((3-ethyl-2-CHI-(2,2, 2-trifluoroethyl)-6,7-di- 20% RAL-hydro-5H-cyclopenta-EtOH PAK IA, 640 [b]pyridin-4-yl)carbamoyl)- in Hex 509 4.6*50 3-fluoro -5-(2-hydroxypro-(0.1% mm; 3-pan-2-yl)thiophene-2- from FA) a sulfonimidamide (R) or (S)-5-(hydroxymethyl)-1-isopropyl-CHI - 50% N'-((1',5',6',7'-tetrahydro-RAL-EtOH 2'H-spiro[cyclopropane-PAK IC, 641 in Hex 445 1,3'-dicyclopenta- 2*25 (0.1% [b,e]pyridin]-8'-cm, 5 of FA)yl)carbamoyl)-1H-pyrazol-a 3-sulfonimidamide (S) or (R)-5-(hydroxymethyl )-1-isopropyl-CHI- 50% N'-((1',5',6',7'-tetrahydro-RAL-EtOH 2'H-spiro[cyclopropane-PAK IC, 642 in Hex 445 1,3'-dicyclopenta-2*25 (0.1% [b,e]pyridin]-8'-cm, 5 of FA) yl)carbamo yl)-1H-pyrazol-a 3-sulfonimidamide (R) or (S)-5-(hydroxymethyl)-1-isopropyl-CHI- 30% N'-(((R)-3-methyl-RAL-EtOH 1,2,3,5,6,7-hexa-PAK IC, 643 in Hex 433 hydrodicyclopen-2*25 (0.1% ta[b,e]pyridin-8-cm, 5 of FA)yl)carbamoyl )-1H-pyrazole- a 3-sulfonimidamide

Ex.

Eluent- LC-MS Structure Name IUPAC Column Nos. [M+H]+ (S) or (R)-5-(hydroxymethyl)-1-isopropyl-CHI- 30% N'-(((R)-3 -methyl-RAL-EtOH 1,2,3,5,6,7-hexa-PAK IC, 644 in Hex 433 hydrodicyclopen-2*25 (0.1% ta[b,e]pyridin-8-cm, 5 of FA)yl)carbamoyl)-1H-pyrazol-a 3-sulfonimidamide (S) or (R)-N'-((3-cyclopropyl-2-CHI-(trifluoromethyl)-6,7-di-30% RAL-hydro-5H-EtOH PAK IC, 645 cyclopenta[b]pyridin-4- in Hex 489 2*25 yl)carbamoyl)-4-(2-(0.2% cm, 5-hydroxypropan-2-DEA) an yl)thiophene-2-sulfonimidamide (R) or (S)-N'-((3-cyclopropyl-2-CHI-(trifluoromethyl)-6,7-di-30% RAL-hydro-5H-EtOH PAK IC, 646 cyclopenta[b]pyridin-4- in Hex 489 2*25 yl)carbamoyl)-4-(2-(0.2% cm, 5 hydroxypropan-2-DEA) an yl)thiophene-2-sulfonimidamide (R) or (S)-1-(2-hydroxyethyl)-N'-((1',5',6',7'-CHI-50% tetrahydro-2'H-RAL-EtOH spiro [cyclopropane-1,3'-PAK IC, 647 in Hex 417 dicyclopenta[b,e]pyridin]-2*25 (0.1% 8'-yl)carbamoyl)-1H-cm, 5 of FA) pyrazol- 3- a (S) or (R)-1 sulfonimidamide -(2-hydroxyethyl)-N'-((1',5',6',7'-CHI- 50% tetrahydro-2'H-RAL-EtOH spiro[cyclopropane-1,3'-PAK IC, 648 in Hex 417 dicyclopenta[b,e]pyridin]-2*25 (0.1% 8'-yl)carbamoyl)-1H-cm, 5 of FA) pyrazol-3-a sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-1-ethyl-4-fluoro-CHI-N'-((3-methyl-2-30% RAL) -(trifluoromethyl)-6,7-di-EtOH PAK IE, 649 hydro-5H- in Hex 435 2*25 cyclopenta[b]pyridin-4-(0.1% cm, 5yl)carbamoyl)-1H-pyrazole - from FA) one; 3-sulfonimidamide (S) or (R)-1-ethyl-4-fluoro-CHI-N'-((3-methyl-2-30% RAL-(trifluoromethyl)-6,7-di-EtOH PAK IE , 650 hydro-5H- in Hex 435 2*25 cyclopenta[b]pyridin-4-(0.1% cm, 5 yl)carbamoyl)-1H-pyrazol- from FA) one; 3-sulfonimidamide (R)-4-((S)-1,2-dihydroxypropan-2-yl)-N'-CHI- 30% ((3,3-dimethyl-1,2,3,5 ,6,7-RAL-EtOH hexa-PAK IG, in Hex 651,465 hydrodicyclopen-2*25 (NH3.Meta[b,e]pyridin-8-cm, 5OH 8yl)carbamoyl)thiophene-2-one mM) sulfonimidamide (S)-4-((S)-1,2-di-CHI-30% hydroxypropan-2-yl)-N'-RAL-EtOH ((3,3-dimethyl-1,2, 3,5,6,7-PAK IG, in Hex 652 hexahydrodicyclo-465 2*25 (NH3.Me penta[b,e]pyridin-8-cm, 5OH 8yl)carbamoyl)thiophene-2-um mM) sulfonimidamide (R)-4-((R)-1,2-di-CHI-hydroxypropan-2-yl)-N'- 30% RAL-((3,3-dimethyl-1,2,3 ,5,6,7- EtOH PAK IG, 653 hexahydrodicyclo- in Hex 465 4.6*50 penta[b,e]pyridin-8-(0.1% mm, 3yl)carbamoyl)thiophene-2- of FA) a sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (S)-4-((R)-1,2-di-CHI-hydroxypropan-2-yl)-N'- 30% RAL - ((3,3-dimethyl-1,2,3,5,6,7-EtOH PAK IG, 654 hexahydrodicyclo- in Hex 465 4.6*50 penta[b,e]pyridin-8-(0 .1% mm, 3 yl)carbamoyl)thiophene-2- from FA) a sulfonimidamide (S) or (R)-(6R)-6-methoxy-N'-((3-methyl-2-CHI-(trifluoromethyl) )-6,7-di-50% RAL-hydro-5H-EtOH PAK IE, 655 cyclopenta[b]pyridin-4- in Hex 475 2*25 yl)carbamoyl)-6,7-di-(0. 1% cm, 5 hydro-5H-pyrazolo[5,1- from FA) a b][1,3]oxazine-3-sulfonimidamide (R) or (S)-(6R)-6-methoxy-N'- ((3-methyl-2-CHI-(trifluoromethyl)-6,7-di-50% RAL-hydro-5H-cyclopenta-EtOH PAK IE, 656[b]pyridin-4-yl)carbamoyl)- in Hex 475 2*25 6,7-dihydro-5H-(0.1% cm, 5 pyrazolo[5,1- from FA) a b][1,3]oxazine-3-sulfonimidamide (R) or (S )-N'-((3-methyl-2-(trifluoromethyl)-6,7-di-CHI- 40% hydro-5H-RAL-EtOH cyclopenta[b]pyridin-4-PAK IC, 657 in Hex 445 yl)carbamoyl)-6,7-di-2*25 (0.1% hydro-5H-pyrazolo[5.1-cm, 5 of FA) b][1,3]oxazine-3 - a (S) or (R)-N'-((3-methyl-2-(trifluoromethyl)-6,7-di-CHI-40% hydro-5H-RAL-EtOH cyclopenta[b]pyridin- 4-PAK IC, 658 in Hex 445 yl)carbamoyl)-6,7-di-2*25 (0.1% hydro-5H-pyrazolo[5.1-cm, 5 FA) b][1,3 ]oxazine-3- a sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-N'-((3-cyclopropyl-2-CHI-(trifluoromethyl)-6,7-di-30% of RAL-hydro-5H-EtOH PAK IF, 659 cyclopenta[b]pyridin-4- in Hex 507 2*25 yl)carbamoyl)-3-fluoro-5-(0.1% cm, 5 (2-hydroxypropan- 2- from FA) an yl)thiophene-2-sulfonimidamide (S) or (R)-N'-((3-cyclopropyl-2-CHI-(trifluoromethyl)-6,7-di-30% RAL-hydro -5H- EtOH PAK IF, 660 cyclopenta[b]pyridin-4- in Hex 507 2*25 yl)carbamoyl)-3-fluoro-5-(0.1% cm, 5 (2-hydroxypropan-2- from FA ) an yl)thiophene-2-sulfonimidamide (S)-4-((R) or (S)-1-CHIRAL 35% hydroxyethyl)-N'-(((R)-3-ART MeOH methyl-1, 2,3,5,6,7-hexa-Cellulo-(NH3.Me 661 hydrodicyclopense-SB, 421 OH 8 ta[b,e]pyridin-8- 2*25 mM) in yl)carbamoyl)thiophene- 2-cm, 5 CO2 sulfonimidamide a (S)-4-((S) or (R)-1-CHIRAL 35% hydroxyethyl)-N'-(((R)-3-ART MeOH methyl-1,2 ,3,5,6,7-hexa-Cellulo-(NH3.Me 662 hydrodicyclopense-SB, 421 OH 8 ta[b,e]pyridin-8- 2*25 mM) in yl)carbamoyl)thiophene-2 - cm, 5 CO2 sulfonimidamide a (R)-4 -((R) or (S)-1-45% hydroxyethyl)-N'-(((R)-3-Reg-MeOH methyl-1,2,3,5,6,7-hexa-AD, (NH3.Me 663 hydrodicyclopen-3*25 421 OH.8 ta[b,e]pyridin-8-cm, 5 mM) in yl)carbamoyl)thiophene-2- a CO2 sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R)-4-((S) or (R)-1- 45% hydroxyethyl)-N'-(((R)-3 - Reg-MeOH methyl-1,2,3,5,6,7-hexa-AD, (NH3.Me 664 hydrodicyclopent-3*25 421 OH.8 ta[b,e]pyridin-8-cm, 5 mM ) in yl)carbamoyl)thiophene-2- a CO 2 sulfonimidamide (R) or (S)-4-acetyl-N'-CHI- 40% of (((R)-3-methyl-1,2,3,5 ,6,7-RAL-MeOH hexa-PAK IC, (NH3.Me 665 hydrodicyclopen-419 2*25 OH 8 ta[b,e]pyridin-8-cm, 5 mM) in yl)carbamoyl)thiophene-2- a CO 2 sulfonimidamide (S) or (R)-4-acetyl-N'-CHI- 40% of (((R)-3-methyl-1,2,3,5,6,7-RAL-MeOH hexa- PAK IC, (NH3.Me 666 hydrodicyclopen-419 2*25 OH 8 ta[b,e]pyridin-8-cm, 5 mM) in yl)carbamoyl)thiophene-2- a CO 2 sulfonimidamide (R) or (S) -4-(2-hydroxypropan-2-yl)-N'-Chiral- 15% of ((2-(trifluoromethyl)-6,7-dipak IC, EtOH 667 hydro-5H-2*25 in Hex 449 cyclopenta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)thiophene-2-one of FA)sulfonimidamide (S) or (R)-4-(2-hydroxypropan-2-yl)-N '- Chiral- 15% ((2-(trifluoromethyl)-6,7-dipak IC, EtOH 668 h hydro-5H-2*25 in Hex 449 cyclopenta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)thiophene-2-um of FA)sulfonimidamide (R) or (S)-1-ethyl -4-fluoro-CHI-N'-(((R)-3-methyl-50% RAL-1,2,3,5,6,7-hexa-EtOH PAK IG, 669 hydrodicyclopen-em Hex 407 2 *25 ta[b,e]pyridin-8-(0.1% cm, 5 yl)carbamoyl)-1H-pyrazole- from FA) a 3-sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (S) or (R)-1-ethyl-4-fluoro-CHI-N'-(((R)-3-methyl-50% of RAL-1,2,3,5,6,7-hexa-EtOH PAK IG, 670 hydrodicyclopen-em Hex 407 2*25 ta[b,e]pyridin-8-(0.1% cm, 5 yl) carbamoyl)-1H-pyrazole- from FA) a 3-sulfonimidamide (R) or (S)-1-ethyl-4-fluoro-N'-((1',5',6',7'-tetrahydro - CHI- 50% 2'H-spiro[cyclopropane-RAL-EtOH 1,3'-PAK IC, 671 in Hex 419 dicyclopenta[b,e]pyridin]- 2*25 (0.1% 8'-yl )carbamoyl)-1H-cm, 5 of FA) pyrazol-3-a sulfonimidamide (S) or (R)-1-ethyl-4-fluoro-N'-((1',5',6',7' -tetrahydro-CHI- 50% 2'H-spiro[cyclopropane-RAL-EtOH 1,3'-PAK IC, 672 in Hex 419 dicyclopenta[b,e]pyridin]-2*25 (0.1% 8'-yl)carbamoyl)-1H-cm, 5 of FA) pyrazol-3- a sulfonimidamide (S) or (R)-2-ethyl-N'-(((R)-CHI- 50% 3- methyl-1,2,3,5,6,7-hexa-RAL-EtOH hydrodicyclopent-PAK IE, 673 in Hex 406 ta[b,e]pyridin-8-3*25 (0.1% yl)carbamoyl) thiazol-5-cm, 5 of FA)sulfonimidamide an (R) or (S)-2-ethyl-N'-(((R)-CHI- 50% of 3-methyl-1,2,3,5, 6, 7-hexa-RAL-EtOH hydrodicyclopen-PAK IE, 674 in Hex 406 ta[b,e]pyridin-8-3*25 (0.1% yl)carbamoyl)thiazol-5-cm, 5 of FA)sulfonimidamide a

Ex. Eluent- LC-MS Structure IUPAC Name Column No. [M+H]+ (S)-5-((R)-1,2-di-

CHIRAL hydroxypropan-2-yl)-3- 30% of

ART fluoro-N'-((1',5',6',7'-EtOH Cellulo-tetrahydro-2'H- in Hex 675 se-SB, 481 spiro[cyclopropane-1,3'- (NH 3 .Me 2*25 dicyclopenta[b,e]pyridin]-OH 8 cm, 5 8'-yl)carbamoyl)thiophene-2-mM) a sulfonimidamide (R)-5-((R)-1,2-di -

CHIRAL hydroxypropan-2-yl)-3- 30% of

ART fluoro-N'-((1',5',6',7'-EtOH Cellulo-tetrahydro-2'H- in Hex 676 se-SB, 481 spiro[cyclopropane-1,3'-(NH 3 .Me 2*25 dicyclopenta[b,e]pyridin]-OH 8 cm, 5 8'-yl)carbamoyl)thiophene-2-mM) a (S)-5-((S)-1,2-disulfonimidamide -

CHIRAL hydroxypropan-2-yl)-3- 30% of

ART fluoro-N'-((1',5',6',7'-EtOH Cellulo-tetrahydro-2'H- in Hex 677 se-SB, 481 spiro[cyclopropane-1,3'-(NH 3 .Me 2*25 dicyclopenta[b,e]pyridin]-OH 8 cm, 5 8'-yl)carbamoyl)thiophene-2-mM) a sulfonimidamide (R)-5-((S)-1,2-di -

CHIRAL hydroxypropan-2-yl)-3- 30% of

ART fluoro-N'-((1',5',6',7'-EtOH Cellulo-tetrahydro-2'H- in Hex 678 se-SB, 481 spiro[cyclopropane-1,3'-(NH 3 .Me 2*25 dicyclopenta[b,e]pyridin]-OH 8 cm, 5 8'-yl)carbamoyl)thiophene-2-mM) a sulfonimidamide (R) or (S)-1-(difluoromethyl)-4- fluoro-CHI- 70% N'-(((R)-3-methyl-RAL-EtOH 1,2,3,5,6,7-hexa-PAK IG, 679 in Hex 429 hydrodicyclopen-4,6* 50 (0.1% ta[b,e]pyridin-8-mm, 3 of FA)yl)carbamoyl)-1H-pyrazole-a 3-sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (S) or (R)-1-(difluoromethyl)-4-fluoro-CHI- 70% N'-(((R)-3 -methyl-RAL-EtOH 1,2,3,5,6,7-hexa-PAK IG, 680 in Hex 429 hydrodicyclopen-4.6*50 (0.1% ta[b,e]pyridin-8-mm , 3 of FA)yl)carbamoyl)-1H-pyrazol-a 3-sulfonimidamide (R) or (S)-1-(difluoromethyl)-4-fluoro-CHI-N'-((1',5',6 ',7'-tetrahydro-30% RAL-2'H-spiro[cyclopropane-EtOH PAK IE, 681 1,3'- in Hex 441 2*25 dicyclopenta[b,e]pyridin]-(0. 1% cm, 5 8'-yl)carbamoyl)-1H- from FA) a pyrazol-3-sulfonimidamide (S) or (R)-1-(difluoromethyl)-4-fluoro-CHI-N'-((1 ',5',6',7'-tetrahydro-30% RAL-2'H-spiro[cyclopropane-EtOH PAK IE, 682 1,3'- in Hex 441 2*25 dicyclopenta[b,e] pyridin]-(0.1% cm, 5 8'-yl)carbamoyl)-1H- from FA) a pyrazol-3-sulfonimidamide (R) or (S)-N'-((2-(1-fluorocyclopropyl)) -3-methyl-CHI- 30% 6,7-dihydro-5H-RAL-EtOH cyclopenta[b]pyridin-4-PAK IG, 683 in Hex 453 yl)carbamoyl)-4-(2-4, 6*50 (0.1% hydroxypropan-2-mm, 3 of FA) yl)thiophene-2-a sulf (S) or (R)-N'-((2-(1-fluorocyclopropyl)-3-methyl-CHI-30% 6,7-dihydro-5H-RAL-EtOH cyclopenta[b]pyridin- 4-PAK IG, 684 in Hex 453 yl)carbamoyl)-4-(2-4.6*50 (0.1% hydroxypropan-2-mm, 3 of FA) yl)thiophene-2-a sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-3-fluoro-N'-((2-(1-fluorocyclopropyl)-CHI- 30% 3-methyl -6,7-dihydro-5H-RAL-EtOH cyclopenta[b]pyridin-4-PAK IE, 685 in Hex 471 yl)carbamoyl)-5-(2-4.6*50 (0.1% hydroxypropan -2-mm, 3 of FA)yl)thiophene-2-a sulfonimidamide (S) or (R)-3-fluoro-N'-((2-(1-fluorocyclopropyl)-CHI-30% 3-methyl -6,7-dihydro-5H-RAL-EtOH cyclopenta[b]pyridin-4-PAK IE, 686 in Hex 471 yl)carbamoyl)-5-(2-4.6*50 (0.1% hydroxypropan -2-mm, 3 of FA)yl)thiophene-2- a sulfonimidamide (R) or (S)-1-ethyl-N'-((1',5',6',7'-tetrahydro- CHI- 50% 2'H-spiro[cyclopropane-RAL-EtOH 1,3'-PAK IC, in Hex 687 401 dicyclopenta[b,e]pyridin]-2*25 (NH 3 .Me 8'-yl)carbamoyl )-1H-cm, 5OH 8 pyrazol-3-one mM)sulfonimidamide (S) or (R)-1-ethyl-N'-((1',5',6',7'-tetrahydro- CHI- 50% 2'H-spiro[cyclopropane-RAL-EtOH 1,3'-PAK IC, in Hex 688 401 dicyclopenta[b,e]pyridin]-2*25 (NH 3 .Me 8'-yl)carbamoyl )-1H-cm, 5OH 8 pyrazol-3-one mM)sulfonimidamide ( R) or (S)-3-Fluoro-5-(2-Column: hydroxypropan-2-yl)-N'-CHI- 20% ((2-(2,2,2-trifluoroethyl)-RAL-EtOH 689 6,7-dihydro-5H-PAK IC, in Hex 481 cyclopenta[b]pyridin-4-2*25 (0.1% yl)carbamoyl)thiophene-2-cm, 5 of FA)sulfonimidamide a

Ex.

Eluent- LC-MS Structure IUPAC Name Column No. [M+H]+ (S) or (R)-3-Fluoro-5-(2-CHI-hydroxypropan-2-yl)-N'- 20% RAL -((2-(2,2,2-trifluoroethyl)-EtOH PAK IC, 690 6,7-dihydro-5H- in Hex 481 2*25 cyclopenta[b]pyridin-4-(0.1% cm , 5 yl)carbamoyl)thiophene-2- from FA) a sulfonimidamide (R) or (S)-1-ethyl-N'-((3-CHI- 30% methyl-2-(trifluoromethyl)-RAL-EtOH 6,7-dihydro-5H-PAK ID, 691 in Hex 417 cyclopenta[b]pyridin-4-2.0*25 (0.1% yl)carbamoyl)-1H-pyrazole-cm, 5 FA) 3-sulfonimidamide an (S) or (R)-1-ethyl-N'-((3-CHI-30% methyl-2-(trifluoromethyl)-RAL-EtOH 6,7-dihydro-5H-PAK ID, 692 in Hex 417 cyclopenta[b]pyridin-4-2.0*25 (0.1% yl)carbamoyl)-1H-pyrazol-cm, 5 of FA) 3-sulfonimidamide an (R) or (S) -1-Methyl-N'-((3-CHI- 30% methyl-2-(trifluoromethyl)-RAL-EtOH 6,7-dihydro-5H-PAK IE, 693 in Hex 403 cyclopenta[b]pyridin -4- 2*25 (0.1% yl)carbamoyl)-1H-pyrazol-cm, 5 of FA) 3-sulfonimidamide an (S) or (R)-1-Methyl-N'-((3-CHI - 30% methyl-2-(trifluoromethyl)-RAL-EtOH 6,7-di-h hydro-5H-PAK IE, 694 in Hex 403 cyclopenta[b]pyridin-4-2*25 (0.1% yl)carbamoyl)-1H-pyrazol-cm, 5 of FA) 3-sulfonimidamide a (R) or (S)-N'-((2,3-CHI-dicyclopropyl-6,7-dihydro-30% RAL-5H-cyclopenta[b]pyridin-EtOH PAK ID, 695 4-yl)carbamoyl)- 1- in Hex 437 2.0*25 (difluoromethyl)-1H-(0.1% cm, 5 pyrazol-3- from FA) a sulfonimidamide

Ex.

Eluent- LC-MS Structure Name IUPAC Column Nos. [M+H]+ (S) or (R)-N'-((2,3-CHI-dicyclopropyl-6,7-dihydro- 30% RAL - 5H-cyclopenta[b]pyridin-EtOH PAK ID, 696 4-yl)carbamoyl)-1- in Hex 437 2.0*25 (difluoromethyl)-1H-(0.1% cm, 5 pyrazol-3- FA) a sulfonimidamide (R) or (S)-N'-((2,3-CHI-dicyclopropyl-6,7-dihydro-50% RAL-5H-cyclopenta[b]pyridin-IPA in PAK ID , 697 4-yl)carbamoyl)-3-fluoro-Hex 479 2.0*25 5-(2-hydroxypropan-2-(0.1% cm, 5 yl)thiophene-2- from FA) a sulfonimidamide (S ) or (R)-N'-((2,3-CHI-dicyclopropyl-6,7-dihydro-50% RAL-5H-cyclopenta[b]pyridin-IPA in PAK ID, 698 4-yl) carbamoyl)-3-fluoro-Hex 479 2.0*25 5-(2-hydroxypropan-2-(0.1% cm, 5 yl)thiophene-2- from FA) a sulfonimidamide 30% of (R) or ( S)-N'-((2,3-CHI-EtOH dicyclopropyl-6,7-dihydro-RAL- in 5H-cyclopenta[b]pyridin-PAK Hex:DC 699 415 4-yl)carbamoyl)-1 -ethyl-1H-ID, 2*25 M=3:1 pyrazol-3-cm, 5 (NH 3 -sulfonimidamide a 10 mM MeOH) 30% of (S) or (R)-N'-((2,3 -CHI-EtOH dicyclopropyl-6,7-dihydro-R AL- in 5H-cyclopenta[b]pyridin-PAK ID, Hex:DC 700 415 4-yl)carbamoyl)-1-ethyl-1H- 2*25 M=3:1 pyrazol-3-cm, 5 (NH 3 - sulfonimidamide a 10 mM MeOH)

Ex. Eluent- LC-MS Structure Name IUPAC Column No. tes [M+H]+ (R) or (S)-2-(2-CHI- 20% hydroxypropan-2-yl)-N'-RAL-EtOH ((2-isopropyl-6,7-dihydro-PAK IE, 701 in Hex 424 5H-cyclopenta[b]pyridin-2*25 (0.1% 3-yl)carbamoyl)thiazol-5-cm, 5 of FA) sulfonimidamide an (S) or (R)-2-(2-CHI- 20% hydroxypropan-2-yl)-N'-RAL-EtOH ((2-isopropyl-6,7-dihydro- PAK IE, 702 in Hex 424 5H-cyclopenta[b]pyridin-2*25 (0.1% 3-yl)carbamoyl)thiazol-5-cm, 5 of FA)sulfonimidamide one (R/S, S) or ( R/S, R)-N'-((3,7-dimethyl-2-(trifluoromethyl)-6,7-di-Chiral- 10% hydro-5H-pak IA, EtOH 703 cyclopenta[b]pyridin- 4-2*25 in Hex 478 yl)carbamoyl)-2-(2-cm, 5 (0.1% hydroxypropan-2-yl)thiazol-one of FA) 5-sulfonimidamide (from Example 273) (R /S, R) or (R/S, S)-N'-((3,7-Dimethyl-2-(trifluoromethyl)-6,7-di-Chiral- 10% hydro-5H-pak IA, EtOH 704 cyclopenta[b]pyridin-4-2*25 in Hex 478 yl)carbamoyl)-2-(2-cm, 5 (0.1% hydroxypropan-2-yl)thiazol-one of FA) 5-sulfonimidamide (a from Example 273) (S, R) or (S, S)-N'-((3,7-

CHIRAL dimethyl-2-(trifluoromethyl)-ART 20% 6,7-dihydro-5H-Cellulo-EtOH cyclopenta[b]pyridin-4-705se-SB, in Hex 478yl)carbamoyl)-2-( 2-2*25 (0.1% hydroxypropan-2-yl)thiazol-cm, 5 of FA) 5-sulfonimidamide (a from Example 704)

Ex. Eluent- LC-MS Structure IUPAC Name Column No. tes [M+H]+ (R, R) or (R, S)-N'-((3,7-

CHIRAL dimethyl-2-(trifluoromethyl)-ART 20% 6,7-dihydro-5H-Cellulo-EtOH cyclopenta[b]pyridin-4-706se-SB, in Hex 478yl)carbamoyl)-2-( 2-2*25 (0.1% hydroxypropan-2-yl)thiazol-cm, 5 of FA) 5-sulfonimidamide (a from Example 704) (R) or (S)-N'-((2, 3-Chiral- 30% dicyclopropyl-6,7-dihydro-pak ID, 5H-cyclopenta[b]pyridin-707 2*25 EtOH in Hex 433 4-yl)carbamoyl)-1-ethyl-4-cm , (0.1% fluoro-1H-pyrazol-3-5um of FA)sulfonimidamide (S) or (R)-N'-((2,3-Chiral-30% dicyclopropyl-6,7-dihydro - pak ID, EtOH 5H-cyclopenta[b]pyridin-708 2*25 in Hex 433 4-yl)carbamoyl)-1-ethyl-4-cm, 5 (0.1% fluoro-1H-pyrazol-3-um of FA)sulfonimidamide (R) or (S)-1-(difluoromethyl)-N'-((3-ethyl-Chiral- 10% 2-(trifluoromethyl)-6,7-dipak ID, EtOH hydro- 5H-709 2*25 in Hex 471 cyclopenta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)-4-fluoro-one of FA) 1H-pyrazol-3-sulfonimidamide (S) or ( R)-1-(difluoromethyl)-N'-((3-ethyl-Chiral- 10% 2-(trifluoromethyl)-6,7-dipak ID, EtOH hydro-5H- 710 2*25 in Hex 471 cyclopenta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)-4-fluoro-one of FA) 1H-pyrazol-3-sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-1-ethyl-4-fluoro-CHI-N'-(((S)-3-methyl-50% of RAL-1,2,3,5,6,7-hexa-IPA in PAK ID, 711 hydrodicyclopen-Hex 407 2*25 ta[b,e]pyridin-8-(0.1% cm, 5 yl) carbamoyl)-1H-pyrazole- from FA) a 3-sulfonimidamide (S) or (R)-1-ethyl-4-fluoro-CHI-N'-(((S)-3-methyl-50% RAL- 1,2,3,5,6,7-hexa-IPA in PAK ID, 712 hydrodicyclopen-Hex 407 2*25 ta[b,e]pyridin-8-(0.1% cm, 5yl)carbamoyl)- 1H-pyrazole- from FA) a 3-sulfonimidamide (R) or (S)-N'-((2-CHI-cyclopropyl-3-methyl-6,7-di-40% RAL-hydro-5H-EtOH PAK IE, 713 cyclopenta[b]pyridin-4- in Hex 407 2*25 yl)carbamoyl)-1-ethyl-4-(0.1% cm, 5-fluoro-1H-pyrazol-3- from FA) a sulfonimidamide (S) or (R)-N'-((2-CHI-cyclopropyl-3-methyl-6,7-di-40% RAL-hydro-5H-EtOH PAK IE, 714 cyclopenta[b]pyridin-4 - in Hex 407 2*25 yl)carbamoyl)-1-ethyl-4-(0.1% cm, 5-fluoro-1H-pyrazol-3- from FA) a sulfonimidamide (R) or (S)-N'- ((3,3-CHI-dimethyl-1,2,3,5,6,7-hexa-40% RAL-hydrodicyclopen-EtOH PAK IE, 715 ta[b,e]pyridin-8- in Hex 421 2*25 yl)carbamoyl)-1-ethyl-4-(0.1% cm, 5-fluoro-1H-pyrazol-3- from FA) a (S) or (R)-N'-((3,3-CHI-dimethyl-1,2,3,5,6,7-hexa-40% RAL-hydrodicyclopen-EtOH PAK IE, 716 ta[ b,e]pyridin-8- in Hex 421 2*25 yl)carbamoyl)-1-ethyl-4-(0.1% cm, 5-fluoro-1H-pyrazol-3- from FA) a sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-1-ethyl-4-fluoro-CHI-N'-((3-methyl-2-(2,2) ,2-50% RAL-trifluoroethyl)-6,7-dihydro-IPA in PAK IE, 717 5H-cyclopenta[b]pyridin-Hex 449 2*25 4-yl)carbamoyl)-1H-(0. 1% cm, 5 pyrazol-3- from FA) a sulphonimide (S) or (R)-1-ethyl-4-fluoro-CHI-N'-((3-methyl-2-(2,2,2- 50% RAL-trifluoroethyl)-6,7-dihydro-IPA in PAK IE, 718 5H-cyclopenta[b]pyridin-Hex 449 2*25 4-yl)carbamoyl)-1H-(0.1% cm , 5-pyrazol-3- from FA) a sulphonimide (S) or (R)-5-(hydroxymethyl)-1-isopropyl-CHI- 15% N'-((3-methyl-2-RAL-EtOH (trifluoromethyl) )-6,7-di-PAK IC, 719 in Hex 461 hydro-5H- 4.6*50 (0.1% cyclopenta[b]pyridin-4-mm, 3 of FA)yl)carbamoyl)-1H- pyrazole-a 3-sulfonimidamide (R) or (S)-5-(hydroxymethyl)-1-isopropyl-CHI- 15% N'-((3-methyl-2-RAL-EtOH(trifluoromethyl)-6,7 -di-PAK IC, 720 in Hex 461 hydro-5H- 4.6*50 (0.1% cyclopenta[b]pyridin-4-mm, 3 of FA) yl)carbamoyl)-1H-pyrazole-a 3- (R) or (S)-1-(difluoromethyl)sulfonimidamide -N'-((3,3-CHI- 15% dimethyl-1,2,3,5,6,7-hexa-RAL-EtOH hydrodicyclopen-PAK 721 in Hex 443 ta[b,e]pyridin-8 - IG, 2*25 (0.1% yl)carbamoyl)-4-fluoro-cm, 5 of FA) 1H-pyrazol-3-a sulfonimidamide

Ex.

Eluent- LC-MS Structure Name IUPAC Column Nos. [M+H]+ (S) or (R)-1-(difluoromethyl)-N'-((3,3-CHI- 15% dimethyl-1,2 ,3,5,6,7-hexa-RAL-EtOH hydrodicyclopen-PAK IG, 722 in Hex 443 ta[b,e]pyridin-8-2*25 (0.1% yl)carbamoyl)-4-fluoro- cm, 5 of FA) 1H-pyrazol-3-a sulfonimidamide (R) or (S)-1-(difluoromethyl)-4-fluoro-CHI- 20% N'-((3-methyl-2-(2) ,2,2-RAL-EtOH trifluoroethyl)-6,7-dihydro-PAK IE, 723 in Hex 471 5H-cyclopenta[b]pyridin-2*25 (0.1% 4-yl)carbamoyl)-1H - cm, 5 of FA) pyrazol-3- a sulfonimidamide (S) or (R)-1-(difluoromethyl)-4-fluoro-CHI- 20% N'-((3-methyl-2-(2, 2,2-RAL-EtOH trifluoroethyl)-6,7-dihydro-PAK IE, 724 in Hex 471 5H-cyclopenta[b]pyridin-2*25 (0.1% 4-yl)carbamoyl)-1H- cm, 5 of FA) pyrazol-3-a sulfonimidamide (S) or (R)-N'-((3,3-CHI- 20% dimethyl-1,2,3,5,6,7-hexa- RAL-EtOH hydrodicyclopen-PAK (NH3.Me 725 ta[b,e]pyridin-8-AS, 433 OH 8 yl)carbamoyl)-1-ethyl-5- 2*25 mM) in (hydroxymethyl)-1H-pyrazole - cm, 5 CO2 3-sulfonimidamide an (R) or (S)-N'-((3,3 - CHI- 20% dimethyl-1,2,3,5,6,7-hexa-RAL-EtOH hydrodicyclopen-PAK (NH3.Me 726 ta[b,e]pyridin-8-AS, 433 OH 8 yl) carbamoyl)-1-ethyl-5-2*25 mM) in (hydroxymethyl)-1H-pyrazol-cm,5CO2 3-sulfonimidamide a

Ex. Eluent-LC-MS Structure IUPAC Name Column No. tes [M+H]+ (R) or (S)-1-CHI-(difluoromethyl)-4-fluoro- 30% RAL-N'-((2 -methyl-3-phenyl-6,7-EtOH PAK IE, 727 dihydro-5H- in Hex 465 2*25 cyclopenta[b]pyridin-4-(0.1% cm, 5 yl)carbamoyl)-1H -pyrazole- from FA) a 3-sulfonimidamide (S) or (R)-1-CHI-(difluoromethyl)-4-fluoro- 30% RAL-N'-((2-methyl-3-phenyl-6, 7- EtOH PAK IE, 728 dihydro-5H- in Hex 465 2*25 cyclopenta[b]pyridin-4-(0.1% cm, 5 yl)carbamoyl)-1H-pyrazole- from FA) a 3- sulfonimidamide

[002643] Compounds 908a, 952a, 983a to 984 and 986 to 1041a in Table 1E can be prepared using one or more methods used to synthesize Examples 1 to 728. Table 64 The examples in the following table were prepared with the use of conditions similar to those described in Example 585 and Scheme XVI from appropriate starting materials. The thiazole tertiary alcohol carbon stereocenters for Examples 729 to 732 were arbitrarily assigned for compound registration purposes.

Exemplary Mass Structure Exact IUPAC Name no [M+H]+ 2-((S)-1,2-dihydroxypropan-2-yl)-N'- (((S)-3-methyl-1, 2,3,5,6,7-hexahydrodicyclopent-ta[b,e]pyridin-8-452yl)carbamoyl)thiazol-5-sulfonimidamide (from chiral Intermediate 117A and Intermediate 262) 2-((S)-1,2-dihydroxypropan-2-yl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopen-730 ta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide (from chiral Intermediate 117A and Intermediate 161) 2-((R)-1,2-dihydroxypropan- 2-yl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl) thiazol-5-sulfonimidamide (from chiral Intermediate 117B and Intermediate 161)

Exemplary Mass Structure Exact IUPAC Name no [M+H]+ 2-((R)-1,2-dihydroxypropan-2-yl)-N'- (((S)-3-methyl-1, 2,3,5,6,7-hexahydrodicyclopent-ta[b,e]pyridin-8-452yl)carbamoyl)thiazol-5-sulfonimidamide (from chiral Intermediate 117B and Intermediate 262) Table 65. The examples in the following table were prepared using conditions similar to those described in Example 252 and Scheme V from appropriate starting materials.

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-Ethyl-4-fluoro-N'-((3-(4-fluorophenyl)-2-(trifluoromethyl)-6,7-dihydro- 5H- 733 515 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 4-Fluoro-1-isopropyl-N'-((3-methyl-2-(trifluoromethyl)-6,7 -dihydro-5H- 734,449 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-(Difluoromethyl)-4-fluoro-N'-((1,2,3,5,6,7-hexahydrodicyclopent-735,415 ta[ b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-ethyl-4-fluoro-N'-((1,2,3,5,6,7-hexahydrodicyclopen-736 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((2,3-dicyclopropyl-6,7-dihydro-5H-cyclopenta[b]pyridin- 4-737yl)carbamoyl)-1-455(difluoromethyl)-4-fluoro-1H-pyrazol-3-sulfonimidamide N'-((3,5-dimethyl-2,6-CF3 bis(trifluoromethyl)pyridi S HN N n-4-yl)carbamoyl)-4-(2-738 N 505 HO hydroxypropan-2-SO CF3 H2N Oyl)thiophene-2-sulfonimidamide

Exemplary Mass- Structure Exact IUPAC Name No [M+H]+ 4-Fluoro-1-isopropyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexa- hydrodicyclopenta[b,e]pyridin-8-739,421yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (from chiral Intermediate 161) 1-(Difluoromethyl)-4-fluoro-N'-((3 -phenyl-2-(trifluoromethyl)-6,7-dihydro-5H- 740 519 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-ethyl-4-fluoro-N '-((2-methyl-3-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-ethyl-4- fluoro-N'-((3-phenyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-Ethyl-N'-((3-ethyl-2-(trifluoromethyl)-6,7-dihydro-5H- 743 cyclopenta[b]pyridin -4- 449 yl)carbamoyl)-4-fluoro-1H-pyrazol-3-sulfonimidamide N'-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide

1-Ethyl-4-fluoro-N'-((3-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

1-Ethyl-4-fluoro-N'-((3-(2-fluorophenyl)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl )-1H-pyrazol-3-sulfonimidamide

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-Ethyl-4-fluoro-N'-((3-(3-fluorophenyl)-2-(trifluoromethyl)-6,7-dihydro- 5H-747515 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 4-Fluoro-N'-(((R)-3-methyl-1,2,3,5,6 ,7-hexa-F hydrodicyclopen-

HN N 748 455 Ph NN ta[b,e]pyridin-8-NSO(R)Oyl)carbamoyl)-1-phenyl-H2N 1H-pyrazol-3-sulfonimidamide 4-Fluoro-N'-((3-methyl) - 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-phenyl-1H-pyrazol-3-sulfonimidamide 4-Fluoro-N'- ((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1-isopropyl-1H-pyrazol-3-sulfonimidamide Table 66 The examples in the table below were prepared using conditions similar to those described in Example 9 and Scheme 2 from appropriate starting materials.

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 5-(N'-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e) ]pyridin-8-751463yl)carbamoyl)sulfamid imidoyl)-N,N-dimethylthiazole-2-carboxamide The examples in the following table were prepared using conditions similar to those described in Example 28 and Scheme 2A to from appropriate starting materials.

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 2-(1,2-dihydroxyethyl)-N'- ((3-methyl-1,2,3,5,6,7-hexa- 752 hydrodicyclopent-438 ta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide 2-(1,2-dihydroxyethyl)-N'-((3,3-dimethyl-1,2, 3,5,6,7-hexa-hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazol-5-sulfonimidamide

Table 68 The examples in the following table were prepared using conditions similar to those described in Example 251 and Scheme IV from appropriate starting materials.

Exemplary Mass Structure Exact IUPAC Name No [M+H]+ 1-Ethyl-4-fluoro-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H- 754,435 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-5-sulfonimidamide Table 69 The examples in the following table were obtained from chiral HPLC resolutions of racemic and diastereomeric mixture examples described above.

The chiral column and eluents are listed in the table.

As a convention, the fastest-eluting enantiomer is always listed first in the table, followed by the slower-eluting enantiomer of the pair.

The symbol * in a chiral center denotes that the chiral center has been separated, and the absolute stereochemistry at that chiral center has not been determined.

The stereochemistry assigned in compound names is provisional.

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-N'-((3,5-dimethyl-2,6- 10% CHIRAL-bis(trifluoromethyl)pyridin) - EtOH PAK IF, 755 4-yl)carbamoyl)-4-(2- in Hex 505 2*25 cm, hydroxypropan-2-(0.1% 5 umyl)thiophene-2- from FA)sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (S) or (R)-N'-((3,5-dimethyl-2,6- 10% CHIRAL-bis(trifluoromethyl)pyridin) - EtOH PAK IF, 756 4-yl)carbamoyl)-4-(2- in Hex 505 2*25 cm, hydroxypropan-2-(0.1% 5 umyl)thiophene-2- from FA)sulfonimidamide (R) or (S)-4-fluoro-1-50% isopropyl-N'-(((R)-3-CHIRAL-EtOH methyl-1,2,3,5,6,7-hexa-PAK IG, in Hex 757 hydrodicyclopen- 421 2*25 cm, (NH 3 .Meta[b,e]pyridin-8-5umOH 8yl)carbamoyl)-1H-pyrazol- mM) 3-sulfonimidamide (S) or (R)- 4-fluoro-1- 50% isopropyl-N'-(((R)-3-CHIRAL-EtOH methyl-1,2,3,5,6,7-hexa-PAK IG, in Hex 758 hydrodicyclopen-421 2*25 cm, (NH3.Meta[b,e]pyridin-8-5umOH 8yl)carbamoyl)-1H-pyrazol-mM) 3-sulfonimidamide (R) or (S)-1-(difluoromethyl) -4-fluoro- 40% CHIRAL-N'-((1,2,3,5,6,7-hexa-EtOH PAK IE, 759 hydrodicyclopen- in Hex 415 2*25 cm, ta[b,e] pyridin-8-(0.1% 5 umyl)carbamoyl)-1H-pyrazol- from FA) 3-sulfonimidamide (S) or (R)-1-(difluoromethyl)-4-fluoro-40% CHIRAL-N '-((1,2,3,5,6,7-hexa-EtOH PAK IE, 760 hydrodicyclopen-em Hex 415 2*25 cm, ta[b,e]pyridin-8-(0.1% 5 umyl)carbamoyl)-1H-pyrazol- from FA) 3-sulfonimidamide (R) or ( S)-1-ethyl-4-50% fluoro-N'-((1,2,3,5,6,7-CHIRAL-EtOH hexa-PAK IG, in Hex 761 hydrodicyclopen- 393 3*25 cm, (NH3.Meta[b,e]pyridin-8-5umOH 8yl)carbamoyl)-1H-pyrazol-mM) 3-sulfonimidamide

Ex.

Eluent- LC-MS Structure Name IUPAC Column Nos. [M+H]+ (S) or (R)-1-ethyl-4- 50% fluoro-N'-((1,2,3,5,6 ,7-CHIRAL-EtOH hexahydrodicyclo-PAK IG, in Hex 762 393 penta[b,e]pyridin-8- 3*25 cm, (NH 3 .Meyl)carbamoyl)-1H-pyrazol-5umOH 8 3 -sulfonimidamide mM) (R) or (S)-N'-((2,3-dicyclopropyl-6,7-di- 15% hydro-5H-Chiralpak EtOH cyclopenta[b]pyridin-4-763 IC, 2 *25 in Hex 455 yl)carbamoyl)-1-cm, 5 µm (0.1% (difluoromethyl)-4-fluoro- from FA) 1H-pyrazol-3-sulfonimidamide (S) or (R)-N'- ((2,3-dicyclopropyl-6,7-di-15% hydro-5H-Chiralpak EtOH cyclopenta[b]pyridin-4-764 IC, 2*25 in Hex 455 yl)carbamoyl)-1-cm, 5 a (0.1% (difluoromethyl)-4-fluoro- from FA) 1H-pyrazol-3-sulfonimidamide (R) or (S)-1-(difluoromethyl)-4-fluoro- 10% N'-(( 3-phenyl-2-CHIRAL-EtOH (trifluoromethyl)-6,7-di-PAK IC, 765 in Hex 519 hydro-5H- 2*25 cm, (0.1% cyclopenta[b]pyridin-4-5um of FA) yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (S) or (R)-1-(difluoromethyl)-4-fluoro- 10% N'-((3-phenyl-2-CHIRAL-EtOH)(trifluoromethyl)-6,7-di-PAK IC, 766 in Hex 519 hydro-5H- 2*25 cm, (0.1% cyclopenta[b]pyridin-4-5 µm of FA)yl)carbamoyl)-1H -pyrazole-3-sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-1-ethyl-4-fluoro-N'-((3-phenyl-2- 20% of (trifluoromethyl)) -6,7-di-Chiralpak EtOH 767 hydro-5H-IC, 2*25 in Hex 497 cyclopenta[b]pyridin-4-cm, 5 µm (0.1% yl)carbamoyl)-1H-pyrazole- from FA ) 3-sulfonimidamide (S) or (R)-1-ethyl-4-fluoro-N'-((3-phenyl-2-20% (trifluoromethyl)-6,7-di-Chiralpak EtOH 768 hydro-5H - IC, 2*25 in Hex 497 cyclopenta[b]pyridin-4-cm, 5 µm (0.1% yl)carbamoyl)-1H-pyrazole- from FA) 3-sulfonimidamide (R) or (S)-1 -ethyl-4- 30% fluoro-N'-((2-methyl-3-CHIRAL-EtOH phenyl-6,7-dihydro-5H-PAK IG, 769 in Hex 443 cyclopenta[b]pyridin-4 - 2*25 cm, (0.1% yl)carbamoyl)-1H-pyrazol-5 um of FA) 3-sulfonimidamide (S) or (R)-1-ethyl-4- 30% fluoro-N'- ((2-methyl-3-CHIRAL-EtOH phenyl-6,7-dihydro-5H-PAK IG, 770 in Hex 443 cyclopenta[b]pyridin-4- 2*25 cm, (0.1% yl) carbamoyl)-1H-pyrazol-5 um of FA) 3-sulfonimidamide (R) or (S)-1-ethyl-N'-((3-ethyl-2-(trifluoromethyl)-6.7-30% di -hydro-5H- Chiralpak EtOH 771 cyclopenta[ b]pyridin-4-IC, 2*25 in Hex 449 yl)carbamoyl)-4-fluoro-cm, 5 µm (0.1% 1H-pyrazol-3- from FA)sulfonimidamide (S) or (R)- 1-Ethyl-N'-((3-ethyl-2-(trifluoromethyl)-6.7-30% dihydro-5H-Chiralpak EtOH 772 cyclopenta[b]pyridin-4-IC, 2*25 in Hex 449 yl)carbamoyl)-4-fluoro-cm, 5 µm (0.1% 1H-pyrazol-3- from FA)sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-N'-((3-cyclopropyl-2-20% (trifluoromethyl)-6,7-di-Chiralpak EtOH hydro-5H- 773 IC, 2*25 in Hex 461 cyclopenta[b]pyridin-4-cm, 5 µm (0.1% yl)carbamoyl)-1-ethyl-4- from FA)fluoro-1H-pyrazole -3-sulfonimidamide (S) or (R)-N'-((3-cyclopropyl-2-20% (trifluoromethyl)-6,7-di-Chiralpak EtOH hydro-5H- 774 IC, 2*25 in Hex 461 cyclopenta[b]pyridin-4-cm, 5 um (0.1% yl)carbamoyl)-1-ethyl-4- from FA) fluoro-1H-pyrazol-3-sulfonimidamide (R) or (S)-N '-((3-cyclopropyl-2-(trifluoromethyl)-6,7-di- 10% CHIRAL-hydro-5H-EtOH PAK IC, 775 cyclopenta[b]pyridin-4- in Hex 483 2*25 cm, yl)carbamoyl)-1-(0.3% 5um (difluoromethyl)-4-fluoro- from FA) 1H-pyrazol-3-sulfonimidamide (S) or (R)-N'-((3-cyclopropyl-2) -(trifluoromethyl)-6,7-di- 10% CHIRAL-hydro-5H-EtOH PAK IC, 776 cyclopenta[b]pyridin-4- in Hex 483 2*25 cm, yl)carbamoyl)-1-(0 .3% 5 um (difluoromethyl)-4-fluoro- from FA) 1H-pyrazol-3-sulfonimidamide

Ex.

Eluent- LC-MS Structure Name IUPAC Column Nos. [M+H]+ (R) or (S)-N'-((3,3-dimethyl-1,2,3,5,6,7-hexa- hydrodicy-20% CHIRAL-clopenta[b,e]pyridin-8-EtOH PAK IG, 777yl)carbamoyl)-4- in Hex 512 2*25 cm, (hydroxymethyl)-2-(1,2,3- (0.1% 5 a trihydroxypropan-2- from FA)yl)thiazol-5-sulfonimidamide (S) or (R)-N'-((3,3-dimethyl-1,2,3,5, 6,7-hexahydrodicyclo-20% CHIRAL-penta[b,e]pyridin-8-EtOH PAK IG, 778 yl)carbamoyl)-4- in Hex 512 2*25 cm, (hydroxymethyl)-2-( 1,2,3-(0.1% 5 a trihydroxypropan-2- from FA)yl)thiazol-5-sulfonimidamide (R) or (S)-1-ethyl-4-fluoro-N'-((3- (2-20% fluorophenyl)-2-CHIRAL-EtOH(trifluoromethyl)-6,7-di-PAK IC, 779 in Hex 515 hydro-5H- 2*25 cm, (0.1% cyclopenta[b]pyridin- 4-5 µm of FA)yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (S) or (R)-1-ethyl-4-fluoro-N'-((3-(2-20% fluorophenyl)- 2-CHIRAL-EtOH (trifluoromethyl)-6,7-di-PAK IC, 780 in Hex 515 hydro-5H- 2*25 cm, (0.1% cyclopenta[b]pyridin-4-5 µm FA) yl )carbamoyl)-1H-pyrazol-3-sulfonimidamide (R) or ( S)-1-ethyl-4-fluoro-N'-((3-(3-20% fluorophenyl)-2-CHIRAL-EtOH(trifluoromethyl)-6,7-di-PAK IC, 781 in Hex 515 hydro- 5H- 3*25 cm, (0.1% cyclopenta[b]pyridin-4-5 um of FA)yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (S) or (R)-1-ethyl-4-fluoro-N'-((3-(3-20% fluorophenyl)-2- CHIRAL-EtOH (trifluoromethyl)-6,7-di-PAK IC, 782 in Hex 515 hydro-5H- 3*25 cm, (0.1% cyclopenta[b]pyridin-4-5 µm FA)yl)carbamoyl )-1H-pyrazol-3-sulfonimidamide (R) or (S)-4-fluoro-N'-((3-methyl-2-20%(trifluoromethyl)-6,7-di-Chiralpak EtOH hydro-5H- 783 IC, 2*25 in Hex 483 cyclopenta[b]pyridin-4-cm, 5 µm (0.1% yl)carbamoyl)-1-phenyl-1H- from FA) pyrazol-3-sulfonimidamide (S) or ( R)-4-fluoro-N'-((3-methyl-2-20% (trifluoromethyl)-6,7-di-Chiralpak EtOH hydro-5H- 784 IC, 2*25 in Hex 483 cyclopenta[b]pyridin -4-cm, 5 µm (0.1% yl)carbamoyl)-1-phenyl-1H- from FA) pyrazol-3-sulfonimidamide (R) or (S)-4-fluoro-N'- 40% (( 1,2,3,5,6,7-hexa-CHIRAL-EtOH hydrodicyclopen-PAK IG, in Hex 785 ta[b,e]pyridin-8- 407 3*25 cm, (NH 3 .Meyl)carbamoyl)- 1-isopropyl-5um OH 8 1H-pyrazol-3-mM)sulfonimidamide (S) or (R)-4-fluoro-N'- 40% ((1,2,3,5,6,7-hexa- CHIRAL- EtOH hydrodicyclopen- PAK IG, in Hex 786 ta[b,e]pyridin-8- 407 3*25 cm, (NH 3 .Meyl)carbamoyl)-1-isopropyl-5um OH 8 1H-pyrazol-3-mM)sulfonimidamide

Ex.

Eluent- LC-MS Structure IUPAC Name Column Nos. [M+H]+ (R) or (S)-1-ethyl-4-fluoro-N'-((3-(4-15% fluorophenyl)-2- Chiralpak EtOH (trifluoromethyl)-6,7-di- 787 IC, 2*25 in Hex 515 hydro-5H-cm, 5 µm (0.1% cyclopenta[b]pyridin-4- from FA)yl)carbamoyl)- 1H-pyrazol-3-sulfonimidamide (S) or (R)-1-ethyl-4-fluoro-N'-((3-(4-15% fluorophenyl)-2-Chiralpak EtOH (trifluoromethyl)-6,7- di-788 IC, 2*25 in Hex 515 hydro-5H-cm, 5 µm (0.1% cyclopenta[b]pyridin-4- from FA)yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (R) or (S)-4-fluoro-1-isopropyl-N'-((3-methyl-2-20% CHIRAL-(trifluoromethyl)-6,7-di-EtOH PAK IE, 789 hydro-5H- in Hex 449 2*25 cm, cyclopenta[b]pyridin-4-(0.1% 5 umyl)carbamoyl)-1H-pyrazole- from FA) 3-sulfonimidamide (S) or (R)-4-fluoro-1-isopropyl -N'-((3-methyl-2-20% CHIRAL-(trifluoromethyl)-6,7-di-EtOH PAK IE, 790 hydro-5H- in Hex 449 2*25 cm, cyclopenta[b]pyridin-4 - (0.1% 5 umyl)carbamoyl)-1H-pyrazol- from FA) 3-sulfonimidamide (R) or (S)-4-fluoro-N'-(((R)-3-methyl-50% 1,2,3,5,6,7-hexa- CHIRAL-EtOH hydrodicyclopen-PAK IE, 791 in Hex 455 ta[b,e]pyridin-8-4.6*50 (0.1% yl)carbamoyl)-1-phenyl-1H-mm, 3 µm FA) pyrazol-3-sulfonimidamide

Ex.

Eluent- LC-MS Structure Name IUPAC Column Nos. [M+H]+ (S) or (R)-4-fluoro-N'- (((R)-3-methyl-50% 1,2,3, 5,6,7-hexa-CHIRAL-EtOH hydrodicyclopen-PAK IE, 792 in Hex 455 ta[b,e]pyridin-8-4,6*50 (0.1% yl)carbamoyl)-1-phenyl-1H - mm, 3 µm of FA) pyrazol-3-sulfonimidamide (R) or (S)-1-ethyl-4-50% fluoro-N'-((3-phenyl-6,7-di-CHIRAL-EtOH hydro) -5H-PAK IE, 793 in Hex 429 cyclopenta[b]pyridin-4- 2*25 cm, (0.1% yl)carbamoyl)-1H-pyrazol-5 µm of FA) 3-sulfonimidamide (S) or ( R)-1-ethyl-4- 50% fluoro-N'-((3-phenyl-6,7-di-CHIRAL-EtOH hydro-5H-PAK IE, 794 in Hex 429 cyclopenta[b]pyridin-4- 2*25 cm, (0.1% yl)carbamoyl)-1H-pyrazol-5 µm FA) 3-sulfonimidamide Example 795 (compound 1100)

N'-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide (Scheme 2) Example 796 (compound 1101)

N'-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-

yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide (Scheme 2) Step 1: Mixture of N-(tert-butyldimethylsilyl)-N'-((3,5-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide and N-(tert-butyldimethylsilyl) -N'-((3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H -pyrazole-3-sulfonimidamide

[002644] To a stirred solution of N-(tert-butyldimethylsilyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide (240mg, 0.78mmol) in THF (10ml) under nitrogen was NaH (60% by weight, 62.8 mg, 1.57 mmol) was added in portions at 0 °C, and then to the above solution, (3,5-dimethyl-2-(trifluoromethyl)- 2,2,2-Trichloroethyl 6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate and (3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro 2,2,2-Trichloroethyl -5H-cyclopenta[b]pyridin-4-yl)carbamate (~1:1 mix, 349 mg, 0.86 mmol) in portions at 0°C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched with 10 ml of water and extracted with 3x10 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. This resulted in 600 mg (crude mixture) of the title compound as a yellow solid. MS-ESI: 563 (M+1). Step 2: N'-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro -1H-pyrazole-3-

sulfonimidamide and N'-((3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazol-3-sulfonimidamide

[002645] To a stirred solution of the mixture of N-(tert-butyldimethylsilyl)-N'-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin -4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide and N-(tert-butyldimethylsilyl)-N'-((3,6-dimethyl-2-(trifluoromethyl)-6 ,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide (600 mg, crude from last step) in DCM (10 ml) HF-pyridine (70% by weight, 0.1 ml) was added dropwise at 0°C. The resulting solution was stirred for 10 min at RT. The resulting mixture was concentrated in vacuo. The crude product was purified by prep HPLC. using the following conditions: Column: Column Xselect CSH OBD 30*150 mm 5 um; Mobile Phase A: water (NH4HCO3 + 0.1%NH3.H2O 10 mM), Mobile Phase B: ACN; Flow rate: 60 ml/min; Gradient: 15% B to 25% B for 10 min; 254/210 nm; Rt1: 8.82 min (Example 795), Rt2: 9.26 min (Example 796). This resulted in 19.3 mg (5.5% over two steps) of Example 795 and 19.5 mg (5.5% over two steps) of Example 796, both as a white solid. MS-ESI: both 449 (M+1). 1

[002646] Example 795 (compound 1100): 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.61 ( sl, 2H), 4.15-4.07 (m, 2H), 3.60-3.40 (m, 1H), 3.08-2.90 (m, 1H), 2.89-2, 79 (m, 1H), 2.30-2.16 (m, 4H), 1.76-1.52 (m, 1H), 1.40-1.34 (m, 1.5H), 1. 09 (d, J = 6.9 Hz, 3H). 1

[002647] Example 796 (compound 1101): 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.04 (d, J = 4.4 Hz, 1H), 7.53 ( sl, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.34-3.05 (m, 1H), 2.95-2.90 (m, 1H), 2.58 -2.38 (m, 3H), 2.21 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H) . Table 70 The examples in the following table were prepared using conditions similar to those described in Example 9 and Scheme 2 from appropriate starting materials.

Exemplary Mass With Structure Exact IUPAC Name at rank at [M+H]+ 4-Fluoro-1-isopropyl-N'- ((1',5',6',7'-tetrahydro-2' H-spiro[cyclopropane-797 1102 433 1,3'-dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((2,3 - dicyclopropyl-6,7-dihydro-5H-cyclopenta[b]pyridin-798 1103 447 4-yl)carbamoyl)-4-fluoro-1-isopropyl-1H-pyrazol-3-sulfonimidamide N'-((3 -cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-799 1104 475 4-yl)carbamoyl)-4-fluoro-1-isopropyl-1H-pyrazol-3-sulfonimidamide 2-(Difluoromethyl)-N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H- 800 1007 456 cyclopenta[b]pyridin-4-yl)carbamoyl)thiazol-5- sulfonimidamide

Table 71. The examples in the following table were prepared using conditions similar to those described in Example 252 and Scheme V from appropriate starting materials.

Exemplary Mass With Structure Exact IUPAC Name at rank no [M+H]+ N'-((2,3-dicyclopropyl-6,7-dihydro-5H-cyclopenta[b]pyridin-801 1106 4- yl)carbamoyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 1-(1,1-Difluoroethyl)-4-fluoro-N'-((3-methyl-2) -(trifluoromethyl)-6,7-dihydro-5H- 802 1004 471 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide N'-((3-cyclopropyl-2-( trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 3 -Fluoro-N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-804 1107 439 yl)carbamoyl)-4-(2-hydroxypropan-2 - yl)thiophene-2-sulfonimidamide

Exemplary Mass- With- Structure Exact IUPAC Name at rank no [M+H]+ 3-Fluoro-4-(2-hydroxypropan-2-yl)-N'-((3-methyl-2-(trifluoromethyl)- 6,7-805 1108 dihydro-5H-481 cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide 3-Fluoro-4-(2-hydroxypropan-2-yl)-N'-( ((R)-3-methyl-1,2,3,5,6,7-hexa-806 1109 453 hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide 3-Fluoro -4-(2-hydroxypropan-2-yl)-N'-((2-methyl-3-phenyl-6,7-dihydro-5H- 807 1110 489 cyclopenta[b]pyridin-4-yl)carbamoyl )thiophene-2-sulfonimidamide 1-(1,1-Difluoroethyl)-4-fluoro-N'-(((R)-3-methyl-1,2,3,5,6,7-hexa-808 1111 hydrodicyclopene - 443 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Exemplary Mass- With- Structure Exact IUPAC Name at rank no [M+H]+ 1-ethyl-4-fluoro-N'- ((2-methyl-3-(trifluoromethyl)-6,7-dihydro- 5H- 809 1012 435 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-(1,1-Difluoroethyl)-4-fluoro-N'-((1,2,3, 5,6,7-hexahydrodicyclopen-810 1112 429 ta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide 1-cyclopropyl-4-fluoro-N'-((3- methyl-2-(trifluoromethyl)-6,7-dihydro-5H- 811 1114 446 cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide Table 72. Examples in the following table were prepared using conditions similar to those described in Example 68 and Scheme 6 from appropriate starting materials.

Exemplary Mass- With- Structure Exact IUPAC Name at rank no [M+H]+ N'-((3-(3,4-difluorophenyl)-2-(trifluoromethyl)-6,7-dihydro-5H- 812 1113 cyclopenta[b]pyridin-4-533yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazol-3-sulfonimidamide

Table 73 The examples in the following table were obtained from chiral HPLC resolutions of racemic and diastereomeric mixture examples described above.

The chiral column and eluents are listed in the table.

As a convention, the fastest-eluting enantiomer is always listed first in the table, followed by the slower-eluting enantiomer of the pair.

The symbol * in a chiral center denotes that the chiral center has been separated, and the absolute stereochemistry at that chiral center has not been determined.

The stereochemistry assigned in compound names is provisional.

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. Test post [M+H]+ (R) or (S)-4-Fluoro-1-isopropyl-N'- ((1',5',6' ,7'-tetra-50% hydro-2'H-Chiral-de espipak ID, EtOH 813 1102a ro[cyclopropane-2*25 in 433 1.3'-cm, 5 Hex dicyclopen-one (0.1 % ta[b,e]pyridin]-8'- of FA)yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (S) or (R)-4-Fluoro-1-isopropyl-N'-((1 ',5',6',7'-tetra- 50% hydro-2'H-Chiral- from espipak ID, EtOH 814 1102b ro[cyclopropane-2*25 at 433 1.3'-cm, 5 Hex dicyclopen-one (0.1% ta[b,e]pyridin]-8'- from FA)yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. Tested [M+H]+ (R) or (S)-N'- ((2,3-dicyclopropyl-6,7-CHI- 30% di- hydro-5H-RAL- of cyclopen-PAK EtOH 815 1103a ta[b]pyridin-4-IC, in 447 yl)carbamoyl)-4- 2*25 Hex fluoro-1-cm, 5 (0.1% isopropyl- 1H- a of FA) pyrazol-3-sulfonimidamide (S) or (R)-N'-((2,3-dicyclopropyl-6,7-CHI- 30% dihydro-5H-RAL- of cyclopen-PAK EtOH 816 1103b ta[b]pyridin-4-IC, in 447 yl)carbamoyl)-4- 2*25 Hex fluoro-1-cm, 5 (0.1% isopropyl-1H-one from FA) pyrazol-3- (R,R) or (R,S)-N'-((3,5-dimethyl-20% 2-(trifluoromethyl)-Chiral-de 6,7-dihydro-5H-pak ID, EtOH cyclopen - 817 1100a 2*25 in 449 ta[b]pyridin-4-cm, 5 Hexyl)carbamoyl)-1-um (0.1% ethyl-4-fluoro-1H- from FA) pyrazol-3-sulfonimidamide ( R, S) or (R, R)-N'-((3,5-dimethyl-20% 2-(trifluoromethyl)-Chiral-de 6,7-dihydro-5H-pak ID, EtOH cyclopen-818 1100b 2*25 in 449 ta[b]pyridin-4-cm, 5 Hexyl)carbamoyl)-1-um (0.1% ethyl-4-fluoro-1H- from FA) pyrazol-3-sulfonimidamide

Ex.

Com- Eluen- LC-MS Structure Name IUPAC Column No. Tested [M+H]+ (S, R) or (S, S)-N'-((3,5-dimethyl-20% 2-(trifluoromethyl) )- Chiral-de 6,7-dihydro-5H-pak ID, EtOH cyclopen-819 1100c 2*25 in 449 ta[b]pyridin-4-cm, 5 Hexyl)carbamoyl)-1-um (0 .1% ethyl-4-fluoro-1H- from FA) pyrazol-3-sulfonimidamide (S, S) or (S, R)-N'-((3,5-dimethyl-20% 2-(trifluoromethyl)- Chiral-de 6,7-dihydro-5H-pak ID, EtOH cyclopen- 820 1100d 2*25 in 449 ta[b]pyridin-4-cm, 5 Hexyl)carbamoyl)-1-one (0.1 % ethyl-4-fluoro-1H- from FA) pyrazol-3-sulfonimidamide (R, R/S)-N'-((3,6-dimethyl-2- 1st peak 20% (trifluoromethyl)- and 2nd of 6 ,7-dihydro-5H-peak, EtOH cyclopen-Chiral-821 1101a in 449 ta[b]pyridin-4-pak ID, Hexyl)carbamoyl)-1-2*25 (0.1% ethyl-4 -fluoro-1H- cm, 5 of FA) pyrazol-3- a sulfonimidamide (S, R) or (S, S)-N'-((3,6-dimethyl-o 3 pi- 20% 2-(trifluoromethyl) )-co, 6,7-dihydro-5H-Chiral-EtOH cyclopen-822 1101b pak ID, in 449 ta[b]pyridin-4-2*25 Hexyl)carbamoyl)-1-cm, 5 ( 0.1% ethyl-4-fluoro-1 H- one of FA) pyrazol-3-sulfonimidamide

Ex. Com- Eluen- LC-MS Structure Name IUPAC Column No. Posted in Tests [M+H]+ (S, S) or (S, R)-N'-((3,6-dimethyl- o 4 pi- 20% 2-(trifluoromethyl)-co, 6,7-dihydro-5H-Chiral-EtOH cyclopent-823 1101c pak ID, in 449 ta[b]pyridin-4-2*25 Hexyl)carbamoyl)- 1-cm, 5 (0.1% ethyl-4-fluoro-1H-one from FA) pyrazol-3-sulfonimidamide (R, R) or (R, S)-N'-((3,6-dimethyl-

CHIRAL ART 2-(Trifluoromethyl)-Amylose-C 6,7-dihydro-5H-NEO, 3*25 cyclopen-cm, 5 um 30% ta[b]pyridin-4-824 1101d of 449 yl)carbamoyl) -1- EtOH:Hex=1: ethyl-4-fluoro-1H-1 (2 mM NH 3 .MeOH pyrazol-3-) in CO 2 sulfonimidamide (Separated from Example 821) (R, S) or (R, R)- N'-((3,6-dimethyl-

CHIRAL ART 2-(Trifluoromethyl)-Amylose-C 6,7-dihydro-5H-NEO, 3x25 cyclopen-cm, 5 um 30% ta[b]pyridin-4-825 1101e of 449 yl)carbamoyl) -1- EtOH:Hex=1: ethyl-4-fluoro-1H-1 (2 mM NH 3 .MeOH pyrazol-3-) in CO 2 sulfonimidamide (Separated from Example 821)

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. Tested [M+H]+ (R) or (S)-N'-((3-cyclopropyl-2-(trifluoromethyl)-CHI- 30% 6, 7-dihydro-5H-RAL-cyclopen-PAK EtOH 826 1104a ta[b]pyridin-4-ID, in 475 yl)carbamoyl)-4-4.6*50 Hex fluoro-1-mm, 3 ( 0.1% isopropyl-1H-one of FA) pyrazol-3-sulfonimidamide (S) or (R)-N'-((3-cyclopropyl-2-(trifluoromethyl)-CHI-30% 6,7-di- hydro-5H-RAL-cyclopen-PAK EtOH 827 1104b ta[b]pyridin-4-ID, in 475 yl)carbamoyl)-4- 4.6*50 Hex fluoro-1-mm, 3 (0.1% isopropyl-1H- a from FA) pyrazol-3-sulfonimidamide (S) or (R)-2-(Difluoromethyl)-CHI- 15% N'-((3-methyl-2-RAL- from (trifluoromethyl)-PAK EtOH 6,7-dihydro-5H- 828 1007b IA, in 456 cyclopent-3*25 Hex ta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)thiazum of FA) ol- 5-sulfonimidamide (R) or (S)-2-(Difluoromethyl)-CHI- 15% N'-((3-methyl-2-RAL-de(trifluoromethyl)-PAK EtOH 6,7-dihydro-5H - 829 1007a IA, in 456 cyclopen- 3*25 Hex ta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)thiazum of FA) ol-5-sulfonymium lady

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. Tested [M+H]+ (R) or (S)-N'- ((2,3-dicyclopropyl-6,7-CHI- 40% di- hydro-5H-RAL- of IPA cyclopen-PAK at 830 1106a ta[b]pyridin-4-ID, 479 Hexyl)carbamoyl)-3- 2.0*25 (0.1% fluoro-4-(2- cm, 5 of FA)hydroxypropan-2-anyl)thiophene-2-sulfonimidamide (S) or (R)-N'-((2,3-dicyclopropyl-6,7-CHI-40% dihydro-5H - RAL- of IPA cyclopen-PAK at 831 1106b ta[b]pyridin-4-ID, 479 Hexyl)carbamoyl)-3- 2.0*25 (0.1% fluoro-4-(2-cm, 5 of FA) hydroxypropan-2-anyl)thiophene-2-sulfonimidamide (R) or (S)-1-(1,1-Difluoroethyl)-4-fluoro-N'-((3-20% methyl-2- Chiral- from IPA (trifluoromethyl)-pak ID, at 832 1004a 6,7-dihydro-5H-2*25,471 Hex cyclopen-cm, 5 (0.1% ta[b]pyridin-4-um from FA ) yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. Test # [M+H]+ (S) or (R)-1-(1,1-Difluoroethyl)-4-fluoro-N'-((3- 20% methyl-2-Chiral- from IPA (trifluoromethyl)-pak ID, at 833 1004b 6,7-dihydro-5H- 2*25 471 Hex cyclopen-cm, 5 (0.1% ta[b]pyridin -4- one of FA)yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide (R) or (S)-N'-((3-cyclopropyl-2-(trifluoromethyl)-CHI-50% 6,7- dihydro-5H-RAL- from IPA cyclopen-PAK at 834 1105a ta[b]pyridin-4- ID 507 Hexyl)carbamoyl)-3-4.6*50 (0.1% fluoro-4-(2 - mm, 3 of FA) hydroxypropan-2-anyl)thiophene-2-sulfonimidamide (S) or (R)-N'-((3-cyclopropyl-2-(trifluoromethyl)-CHI-50% 6,7- dihydro-5H-RAL- from IPA cyclopen-PAK at 835 1105b ta[b]pyridin-4- ID 507 Hexyl)carbamoyl)-3-4.6*50 (0.1% fluoro-4-(2 - mm, 3 of FA) hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. Test # [M+H]+ (S) or (R)-N'-((3-(3,4-difluorophenyl)-2-CHI- 20% (trifluoromethyl)-RAL- from IPA 6,7-dihydro-5H-PAK at 836 1113a cyclopen-IG 533 Hex ta[b]pyridin-4-2*25 (0.1% yl)carbamoyl)-1- cm, 5 of FA) ethyl-4-fluoro-1H- a pyrazol-3-sulfonimidamide (R) or (S)-N'-((3-(3,4-difluorophenyl)-2-CHI-20% ( trifluoromethyl)-RAL- from IPA 6,7-dihydro-5H-PAK at 837 1113b cyclopen-IG 533 Hex ta[b]pyridin-4-2*25 (0.1% yl)carbamoyl)-1-cm , 5 of FA) ethyl-4-fluoro-1H- a pyrazol-3-sulfonimidamide (R) or (S)-3-fluoro-N'-((1,2,3,5,6,7-CHI- 30% hexa-RAL- of hydrodicyclopen-PAK EtOH 838 1107a ta[b,e]pyridin-8-IG in 439 yl)carbamoyl)-4- 2*25 Hex (2-cm, 5 (0.3% hydroxypropan- 2- one of FA) yl)thiophene-2-sulfonimidamide

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. No. [M+H]+ (S) or (R)-3-fluoro-N'- ((1,2,3,5,6,7- CHI-30% hexa-RAL- from hydrodicyclopen-PAK EtOH 839 1107b ta[b,e]pyridin-8-IG in 439 yl)carbamoyl)-4- 2*25 Hex (2-cm, 5 (0.3% FA)yl)thiophene-2-sulfonimidamide (R) or (S)-3-fluoro-4-(2-hydroxypropan-2-CHI-15%yl)-N'-((3- methyl-2-RAL- from (trifluoromethyl)-PAK EtOH 840 1108a 6,7-dihydro-5H-IG in 481 cyclopen-2*25 Hex ta[b]pyridin-4-cm, 5 (0.1% yl)carbamoyl)thiophenone of FA)no-2-sulfonimidamide (S) or (R)-3-fluoro-4-(2-hydroxypropan-2-CHI-15% yl)-N'-((3-methyl -2- RAL- of (trifluoromethyl)-PAK EtOH 841 1108b 6,7-dihydro-5H-IG in 481 cyclopen- 2*25 Hex ta[b]pyridin-4-cm, 5 (0.1% yl )carbamoyl)thiophenone from FA) no-2-sulfonimidamide

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. Test # [M+H]+ (R) or (S)-3-fluoro-4-(2-hydroxypropan-2-CHI- 30% yl)-N '-(((R)-3-RAL- from methyl-1,2,3,5,6,7-PAK EtOH 842 1109a hexa-IG in 453 hydrodicyclopen- 2*25 Hex ta[b,e]pyridin- 8-cm, 5 (0.3%yl)carbamoyl)thiophenone of FA)no-2-sulfonimidamide (S) or (R)-3-fluoro-4-(2-hydroxypropan-2-CHI- 30%yl )-N'-(((R)-3-RAL- from methyl-1,2,3,5,6,7-PAK EtOH 843 1109b hexa-IG in 453 hydrodicyclopen- 2*25 Hex ta[b,e ]pyridin-8-cm, 5 (0.3% yl)carbamoyl)thiophenone of FA) no-2-sulfonimidamide (S) or (R)-3-fluoro-4-(2-CHI-hydroxypropan-2- RAL 15% yl)-N'-((phenyl-6,7-diCellulo-EtOH 2-methyl-3-ART 844 1110a hydro-5H-lose- in 489 cyclopen-SB, Hex ta[b]pyridin -4- 2*25 (0.3% yl)carbamoyl)thiophen cm, 5 of FA) no-2- a sulfonimidamide

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. No. [M+H]+ (R) or (S)-3-fluoro-4-(2-CHI-hydroxypropan-2-RAL 15% yl)- N'-((phenyl-6,7-di-Cellulo-EtOH 2-methyl-3-ART 845 1110b hydro-5H-lose- in 489 cyclopen-SB, Hex ta[b]pyridin-4-2*25 (0.3% yl)carbamoyl)thiophen cm, 5% FA) no-2-asulfonimidamide (R) or (S)-1-(1,1-difluoroethyl)-CHI-40% 4-fluoro-N' - RAL-de ((1,2,3,5,6,7-PAK EtOH hexa- 846 1115a IG in 429 hydrodicyclopen- 2*25 Hex ta[b,e]pyridin-8-cm, 5 (0.1 % yl)carbamoyl)-1H- a from FA) pyrazol-3-sulfonimidamide (S) or (R)-1-(1,1-difluoroethyl)-CHI-40% 4-fluoro-N'-RAL- from ( (1,2,3,5,6,7-PAK EtOH hexa-847 1115b IG in 429 hydrodicyclopen- 2*25 Hex ta[b,e]pyridin-8-cm, 5 (0.1% yl)carbamoyl) -1H- one of FA)pyrazol-3-sulfonimidamide 50% (R) or (S)-1-ethyl- of 4-fluoro-N'-((2-CHI-EtOH methyl-3-RAL- in (trifluoromethyl) )-PAK Hex:D 6,7-dihydro-5H-848 1116a IE, CM= 435 cyclopent-2*25 3:1 ta[b]pyridin-4-cm, 5 (NH 3 .M yl)carbamoyl) -1H- a pyrazol-3- sulfonimidami eOH of mm)

Ex.

Com- Eluen- LC-MS Structure IUPAC Name Column No. Test # [M+H]+ 50% (S) or (R)-1-ethyl- of 4-fluoro-N'-((2-CHI-EtOH methyl-3-RAL- in (trifluoromethyl)-PAK Hex:D 6,7-dihydro-5H- 849 1116b IE, CM= 435 cyclopen-2*25 3:1 ta[b]pyridin-4-cm, 5 (NH 3 .M yl)carbamoyl)-1H- an eOH pyrazol-3- 10 mM sulfonimidamide) (R) or (S)-1-(1,1-difluoroethyl)-4-fluoro-N'-((( R)-CHI-50% 3-methyl-RAL- from IPA 1,2,3,5,6,7-PAK at 850 1117a hexa-IE, 443 Hex hydrodicyclopen-2*25 (0.1% ta[b ,e]pyridin-8-cm, 5 of FA)yl)carbamoyl)-1H- a pyrazol-3-sulfonimidamide (S) or (R)-1-(1,1-difluoroethyl)-4-fluoro-N' -(((R)-CHI-50% 3-methyl-RAL- from IPA 1,2,3,5,6,7-PAK in 851 1117b hexa-IE, 443 Hex hydrodicyclopen-2*25 (0.1 % ta[b,e]pyridin-8-cm, 5 of FA) yl)carbamoyl)-1H- a pyrazol-3-sulfonimidamide Table 73A The examples in the following table were obtained from chiral HPLC resolutions of examples of racemic and diastereomeric mixture described above.

The chiral column and eluents are listed in the table.

As a convention, the fastest-eluting enantiomer is always listed first in the table, followed by the slower-eluting enantiomer of the pair.

The symbol * in a chiral center denotes that the chiral center has been separated, and the absolute stereochemistry at that chiral center has not been determined.

The stereochemistry assigned in compound names is provisional.

Ex.

LC-MS Structure IUPAC Name Column Eluents # [M+H]+ (R) or (S)-1-cyclopropyl-4-fluoro- 20% N'-((1,2,3,5,6,7 - EtOH in hexa-Chiralpak Hex:DC 863 hydrodicyclopen-IC, 2*25 M=3:1 405 ta[b,e]pyridin-8-cm, 5 µm (NH 3 .Meyl)carbamoyl)-1H-OH 10 pyrazol-3-mM)sulfonimidamide (S) or (R)-1-cyclopropyl-4-fluoro-20% N'-((1,2,3,5,6,7-EtOH in hexa-Chiralpak Hex: DC 864 hydrodicyclopen-IC, 2*25 M=3:1 405 ta[b,e]pyridin-8-cm, 5 µm (NH 3 .Meyl)carbamoyl)-1H-OH 10 pyrazol-3-mM)sulfonimidamide ( R) or (S)-1-cyclopropyl-4-fluoro-N'-((1',5',6',7'-tetra-20% hydro-2'H-EtOH in spiro[cyclopropane-Chiralpak) Hex:DC 865 1,3'-ID, 2*25 M=3:1 431 dicyclopen-cm, 5 µm (NH 3 .Me ta[b,e]pyridin]-8'-OH 10yl)carbamoyl)-1H - mM) pyrazol-3-sulfonimidamide

Ex. LC-MS Structure IUPAC Name Column Eluents # [M+H]+ (S) or (R)-1-cyclopropyl-4-fluoro-N'-((1',5',6',7'- tetra-20% hydro-2'H-EtOH in spiro[cyclopropane-Chiralpak Hex:DC 866 1,3'-ID, 2*25 M=3:1 431 dicyclopen-cm, 5 µm (NH 3 .Me ta[ b,e]pyridin]-8'-OH 10yl)carbamoyl)-1H-mM) pyrazol-3-sulfonimidamide (R) or (S)-1-cyclopropyl-4-fluoro-20% N'-(( (R)-3-Methyl-EtOH in CHI-1,2,3,5,6,7-hexa-Hex:DC

RALPAK 867 hydrodicyclopen-M=3:1 419 ID, 2*25 ta[b,e]pyridin-8-(NH 3 .Me cm, 5 um yl)carbamoyl)-1H-OH 10 pyrazol-3-mM)sulfonimidamide ( S) or (R)-1-cyclopropyl-4-fluoro- 20% N'-(((R)-3-methyl-EtOH in CHI- 1,2,3,5,6,7-hexa-Hex :A.D

RALPAK 868 hydrodicyclopen-M=3:1 419 ID, 2*25 ta[b,e]pyridin-8-(NH 3 .Me cm, 5 um yl)carbamoyl)-1H-OH 10 pyrazol-3-mM)sulfonimidamide ( R) or (S)-1-cyclopropyl-4-fluoro-N'-((3-methyl-2-30% CHI-(trifluoromethyl)-6,7-EtOH in

RALPAK 869 dihydro-5H-Hex 447 IE, 2*25 cyclopenta[b]pyridin-(0.1% cm, 5 um 4-yl)carbamoyl)-1H-FA) pyrazol-3-sulfonimidamide

Ex. LC-MS Structure IUPAC Name Column Eluents # [M+H]+ (S) or (R)-1-cyclopropyl-4-fluoro-N'-((3-methyl-2-30% CHI- ( trifluoromethyl)-6,7-EtOH in

RALPAK 870 dihydro-5H-Hex 447 IE, 2*25 cyclopenta[b]pyridin-(0.1% cm, 5 um 4-yl)carbamoyl)-1H-FA) pyrazol-3-sulfonimidamide (R) or (S)-N'-((2,3-bis(trifluoromethyl)-30% CHI-6,7-dihydro-5H-EtOH in

RALPAK 871 cyclopenta[b]pyridin-Hex 489 IE, 2*25 4-yl)carbamoyl)-1-ethyl-(0.1% cm, 5 um 4-fluoro-1H-pyrazol-FA) 3-sulfonimidamide ( S) or (R)-N'-((2,3-bis(trifluoromethyl)-30% CHI-6,7-dihydro-5H-EtOH in

RALPAK 872 cyclopenta[b]pyridin-Hex 489 IE, 2*25 4-yl)carbamoyl)-1-ethyl-(0.1% cm, 5 um 4-fluoro-1H-pyrazol-FA) 3-sulfonimidamide Table 74. The examples in the following table were prepared using conditions similar to those described in Example 252 and Scheme V from appropriate starting materials. Exemplary Mass With Structure Exact IUPAC Name at rank no [M+H]+ N'-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H- 852 1118 cyclopenta[b] pyridin-4-474yl)carbamoyl)-2-(trifluoromethyl)thiazol-5-sulfonimidamide

Exemplary Mass- With- Structure Exact IUPAC Name at rank at [M+H]+ 4-Fluoro-1-((R)-2-hydroxypropyl)-N'- ((1',5',6',7 '-Tetrahydro-2'H-853 1119 spiro[cyclopropane-1,3'-449 dicyclopenta[b,e]pyridin]-8'-yl)carbamoyl)-1H-pyrazol-3-sulfonimidamide The following protocol it is suitable for testing the activity of the compounds disclosed in this document. Procedure 1: Production of IL-1β in Gramicidin-stimulated PMA-differentiated THP-1 cells.

[002648] THP-1 cells were purchased from the American Type Culture Collection and subcultured according to the supplier's instructions. Cells were cultured in complete RPMI 1640 (containing 10% heat-inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml) and maintained in log phase prior to experimental setup. compounds were dissolved in dimethylsulfoxide (DMSO) to generate a stock of 30 mM. The stock of compound was first prediluted in DMSO to intermediate concentrations of 3, 0.34, 0.042 and 0.0083 mM and subsequently detected with using an Echo550 liquid handler on an empty 384-well assay plate to achieve the desired final concentration (e.g., 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 μM.) DMSO was filled into the plate to reach a final assay concentration of 0.37% DMSO. The plate was then sealed and stored at room temperature until needed.

[002649] THP-1 cells were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16 to 18 hours. On the day of the experiment, the medium was removed and the adherent cells were detached with trypsin for 5 minutes. The cells were then harvested, washed with complete RPMI 1640, centrifuged and resuspended in RPMI 1640 (containing 2% heat-inactivated FBS, penicillin (100 units/ml) and streptomycin (100 µg/ml). cells were placed in the 384-well plate containing the stained compounds at a density of 50,000 cells/well (final assay volume 50 µl) Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5 µM ) (Enzo) for 2 h. The plates were then centrifuged at 340 g for 5 min. The cell-free supernatant (40 µl) was collected using a 96-channel PlateMaster (Gilson) and the - IL-1β induction was evaluated by HTRF (cisbio) Plates were incubated for 18 hours at 4 ºC and read using the predefined HTRF program (donor emission at 620 nm, acceptor emission at 668 nm) from the SpectraMax i3x spectrophotometer (Molecular Devices, SoftMax 6 software). RID3 (100 - 0.0017 μM) were run simultaneously with each experiment. Data were normalized to samples treated with vehicle (equivalent to 0% inhibition) and 100 µM CRID3 (equivalent to 100% inhibition). The compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA-differentiated THP-1 cells. Procedure 2: Production of IL-1β in Gramicidin-stimulated PMA-differentiated THP-1 cells.

[002650] THP-1 cells were purchased from the American Type Culture Collection and subcultured according to the supplier's instructions. Prior to experiments, cells were cultured in complete RPMI 1640 (containing 10% heat-inactivated FBS, penicillin (100 units/ml) and streptomycin (100 µg/ml) and maintained in log phase prior to experimental setup. Prior to the experiment, THP-1 cells were treated with PMA (Phorbol 12-myristate 13-

acetate) (20 ng/ml) for 16 to 18 hours. Compounds were dissolved in dimethylsulfoxide (DMSO) to generate a 30 mM stock. On the day of the experiment, the medium was removed and the adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, centrifuged, resuspended in RPMI 1640 (containing 2% heat-inactivated FBS, penicillin (100 units/ml) and streptomycin (100 µg/ml). cells were placed in a 384-well plate at a density of

50,000 cells/well (final assay volume 50 µl). Compounds were first dissolved in the assay medium to obtain a 5x maximum concentration of 500 µM. 10-step dilutions (1:3) were then performed in assay medium containing 1.67% DMSO. Solutions of 5x compounds were added to the culture medium to achieve the desired final concentration (e.g., 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0, 0051, 0.0017 µM). The final DMSO concentration was 0.37%. Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5 μM) (Enzo) for 2 hours. The plates were then centrifuged at 340 g for 5 min. Cell-free supernatant (40 µl) was collected using a 96-channel PlateMaster (Gilson) and IL-1β production was evaluated by HTRF (cisbio). A vehicle-only control and a CRID3 dose titration (100 - 0.0017 μM) were performed simultaneously with each experiment. Data were normalized to samples treated with vehicle (equivalent to 0% inhibition) and 100 µM CRID3 (equivalent to 100% inhibition). The compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA-differentiated THP-1 cells.

[002651] Tables B1, B2, B3 and B4 show the biological activity of compounds in hTHP-1 assay containing 2% fetal bovine serum. Tables B5 and B6 show the biological activity of compounds in hTHP-1 assay that contain 10% fetal bovine serum.

Caption: <0.008 µM = "++++++"; ≥0.008 and <0.04 µM = "+++++"; ≥0.04 and <0.2 µM = "++++"; ≥0.2 and <1 µM = "+++"; ≥1 and <5 µM = "++"; ≥5 and <30 µM = "+". ND = not determined.

Table B1. Mean IC50 of Compounds in the hTHP-1 Assay Example in Compound Number IC50 of hTHP-1 1 165 ++ 2 165a +++ 3 165b + 4 163 +++ 5 128 +++ 6 110 + 7 164 ++ 8 167 ++ 9 159 ++ 10 135 ++ 11 119 ++ 12 122 +++ 13 125 ++ 14 126 ++++ 15 101 ++++ 16 114 ++++ 17 117 + 18 116 + 19 130 + 20 170 ++ 21 171 ++ 22 172 +++ 23 173 +++ 24 174 +++ 25 175 +++ 26 176 + 27 177 +

Example in Compound Number IC50 of hTHP-1 28 118 ++ 29 150 ++ 30 121 +++ 31 178 + 32 179 ++ 33 34 107 +++ 35 155 ++++ 36 166 + 37 149 +++ 38 105 ++++ 39 141 ++++ 40 103 ++++ 41 127 ++++ 42 102 ++++ 43 131 +++ 44 123 ++ 45 180 ++ 46 113 > 30 47 181 + ++ 48 182 > 14 49 183 + 50 154 +++ 51 120 +++ 52 162 ++++ 53 104 +++ 54 168 +++ 55 158 ++ 56 157 + 57 156 > 30 58 160 + 59 129 +++

Example in Compound Number IC50 of hTHP-1 60 161 ++ 61 153 ++++ 62 152 +++ 63 151 +++ 64 147 + 65 146 + 66 133 > 14 67 112 > 30 68 115 ++ 69 106 ++++ 70 148 ++++ 71 132 > 27 72 140 ++++ 73 139 +++ 74 134 ++ 75 145 + 76 144 > 30 77 143 > 30 78 142 > 30 79 138 + 80 137 > 30 81 136 ++++ 82 124 +++ 83 128a +++ 84 128b + 85 150a + 86 150b +++ 87 163a ++++ 88 163b + 91 167a + 92 167b +++ 93 164b +

Example in Compound Number IC50 of hTHP-1 94 164a ++ 95 161a + 96 161b ++ 97 159a ++ 98 159b + 99 158a ++ 100 158b > 30 101 157a > 30 102 157b + 103 160a ++ 104 104 105 162ab ++ 106 162aa + 107 162bb ++++ 108 162ba +++ 109 156a > 30 110 156b ++ 111 155a ++++ 112 155b ++ 113 149a +++ 114 149b > 30 115 106a +++ + 116 106b ++ 117 148a +++ 118 148b ++ 119 147a > 30 120 147b ++ 121 107a +++ 122 107b + 123 145a +++ 124 145b ++ 125 105a ++++

Example in Compound Number IC50 of hTHP-1 126 105b ++ 127 153a + 128 153b ++++ 129 133a > 30 130 133b > 30 131 137a > 10 132 137b > 30 133 136a ++ 134 136b ++++ 13 140a ++++ 136 140b + 137 140aa ++++ 138 140ab ++ 139 140ba + 140 140bb > 30 141 129aa ++++ 142 129ab > 30 143 129ba ++ 144 129bb + 145 127a ++ 12 74 ++ 147 130a > 30 148 130b ++ 149 126a ++++ 150 126b + 151 168a + 152 168b +++ 153 141b ++++ 154 141a ++ 155 141aa +++++ 156 141ab +++ 157 141ba ++

Example in Compound Number IC50 of hTHP-1 158 141bb + 159 104a +++ 160 104b + 161 168aa + 162 168ab > 30 163 168ba +++ 164 168bb ++ 165 122a ++++ 166 122b + 167 103aa ++ 168 103ab + 169 103ba +++++ 170 103bb +++ 171 102a ++ 172 102b +++++ 173 101a ++ 174 101b +++++ 175 125a > 30 176 125b ++ 177 132a + 178 132b > 30 179 131b + 180 131a +++ 181 131aab +++ 182 131c + 183 131d + 184 131e + 185 131f ++ 186 131g +++ 187 121a ++++ 188 121b + 189 169a +

Example in Compound Number IC50 of hTHP-1 190 169b ++++ 191 119a ++ 192 119b > 30 193 118a +++ 194 118b > 24 195 134aa > 30 196 134ab > 30 197 134ba ++ 198 134 bb + 1 > 30 200 117b + 201 172a + 202 172b +++ 203 173a +++ 204 173b > 20 205 183a ++ 206 183b > 30 207 183c + 208 183d > 30 209 116a > 30 210 1 ++ 212 114b ++ 213 124a + 214 124b +++ 215 154a ++ 216 154b > 28 217 120a > 30 218 120b > 30 219 142a > 30 220 142b > 30 221 143a > 30

Example in Compound Number IC50 of hTHP-1 222 143b > 30 223 184a ++++ 224 184b + 225 184c + 226 184d ++ 227 174a + 228 174b ++++ 229 175a + 230 175b +++ 231 180a + ++ 232 180b > 30 33 111 > 30 185b > 30 185a + 185 > 30 201a ++++

Table B2 Example in Compound at IC50 of hTHP-1 (uM) 233 652 ++ 234 652b > 30 235 652a +++ 236 695 + 237 643 + 238 201 +++ 239 640 +++ 240 605 +++ 241 605f +++ 242 605a +++ 243 691 ++ 244 688 ++ 245 676 ++

Example in Compound at IC50 of hTHP-1 (uM) 246 669 + 247 612 ++ 248 627 +++ 249 607 ++ 250 665 > 30 251 693 ++ 252 645 ++++ 253 672 + 254 702 ++ 255 692 ++ 256 656 ++ 257 681 ++++ 258 668 + 259 658 + 260 667 +++ 261 703 + 262 664 ++ 263 632 +++ 264 624 ++++ 265 631 ++++ 266 630 +++ 267 623 +++ 268 621 ++ 269 629 ++ 270 610 + 271 611 +++ 272 609 ++ 273 608 ++ 274 616 ++++ 275 604 +++ 276 603 ++++ 277 304 ++

Example in Compound at IC50 of hTHP-1 (uM) 278 306 + 279 677 ++ 280 661 ++ 281 647 ++ 282 619 + 283 618 ++ 284 626 ++++ 285 696 + 286 682 ++ 287 653 ND 288 641 + 289 694 ++ 290 687 + 291 660 + 292 140c +++ 293 635 + 294 689 ++ 295 642 ++++ 296 686 +++ 297 680 ++ 298 674 ++ 299 684 +++ 300 683 ++ 301 679 + 302 673 + 303 704 ++ 304 664 + 305 663 ++ 306 651 + 307 659 ++ 308 662 + 309 649 +

Example in Compound at IC50 of hTHP-1 (uM) 310 650 +++ 311 648 ++ 312 615 ++ 313 620 + 314 185 > 30 315 690 ++ 316 675 ++ 317 678 ++ 318 671 ++ 319 657 + 320 670 +++ 321 655 + 322 654 +++ 323 634 ++++ 324 639 ++ 325 646a ++ 326 638 + 327 637 + 328 633 > 30 329 625 + 330 622 + 331 628 +++ 332 617 + 333 614 +++ 334 613 +++ 335 602 ++ 336 636c +++ 337 601 + 338 685 ++ 339 685b ++ 340 685a > 30 341 694b ++

Example in Compound at IC50 of hTHP-1 (uM) 342 694a > 30 343 687b + 344 687a > 30 345 689b + 346 689a > 30 347 642b ++++ 348 642a + 349 686b + 350 686a +++ 351 352 170a +++ 353 680b ++ 354 680a + 355 682b ++ 356 682a > 30 357 653b > 30 358 653a + 359 674b ++ 360 674a > 30 361 684b + 362 634a ++6 3 ++ 365 673b > 30 366 673a ++ 367 705b ++ 368 705a + 369 664b ++ 370 664a > 30 371 663b ++ 372 663a > 30 373 651b ++

Example in Compound at IC50 of hTHP-1 (uM) 374 651a + 375 659b +++ 376 659a + 377 649b > 30 378 649a + 379 650b + 380 650a ++++ 381 648b > 30 382 648a +++ 383 6b ++ 384 615A> 30 385 620B + 386 620A> 30 387 185A + 388 185B + 388 185B + 390 115A + 391 701B> 30 392 701A + 393 692B + 395 695B + 396 695A> 30 397 691b ++ 398 691a + 399 688b + 400 688a +++ 401 690b ++ 402 690a > 30 403 661b + 404 661a +++ 405 647b > 30

Example in Compound at IC50 of hTHP-1 (uM) 406 647a ++ 407 676b ++ 408 676a > 30 409 181b ++++ 410 181a ++ 411 675b + 412 675a ++ 413 681b +++ 414 681a ++ 415 669B + 416 669A> 30 417 176B ++ 418 176A> 30 419 182B + 420 182A> 30 421 678B> 30 422 678A ++ 423 658B ++ 424 658A> 30 425 667B +++ 426 667A + 427 657B + 428 657a > 30 429 670b ++++ 430 670a + 431 612b ++ 432 612a > 30 433 626b ++++ 434 626a + 435 665b ++ 436 665a > 30 437 654b +++

Example in Compound at IC50 of hTHP-1 (uM) 438 654a ++ 439 634b ++++ 440 634a + 441 639b +++ 442 639a > 30 443 700b +++ 444 700a > 30 445 638b > 30 446 638a + + 447 637b > 30 448 637b ++ 449 645b + 450 645a ++++ 451 644b ++ 452 644a > 30 453 633b + 454 633a > 30 455 625b ++ 456 625a > 30 453 633b + 454 633a > 30 455 625b ++ 456 625a > 30 457 ++63 459 624b ++++ 460 624a ++ 461 631b ++++ 462 631a + 463 630b +++ 464 630a + 465 623b + 466 623a ++++ 467 622b + 468 622a + 469 621b ++

Example in Compound at IC50 of hTHP-1 (uM) 470 621a + 471 618b +++ 472 618a > 30 473 628b +++ 474 628a > 30 475 617b > 30 476 617a + 477 610b + 478 610a 6 ++ 1 479 ++ 480 611a + 481 698b +++ 482 698a ++ 483 616b + 484 616a ++++ 485 614b ++ 486 614a ++++ 487 613b ++ 488 613a ++++ 489 697b ++++ 490 697a + 491 607b ++ 492 607a > 30 493 636b ++++ 494 636a + 495 304b ++ 496 304a > 30 497 306b + 498 306a + 499 605e + 500 605c +++ 501 605g

Example in Compound at IC50 of hTHP-1 (uM) 502 605h +++ 503 660d + 504 660c > 30 505 660b > 30 506 660a > 30 507 201f + 508 201e ++++ 509 201d + 510 201c 20 + 511 ++++ 512 201b ++++ 513 662c ND 514 662e ++ 515 662d + 516 662b > 30 517 662a > 30 518 699c + 519 699b +++++ 520 699a > 30 521 640c ++ 522 ++ ++ 523 640a +++++ 524 656d ++ 525 656b + 526 656a +++ 527 656c + 528 668c + 529 668b + 530 668a > 30 531 668d > 30 532 671d +++ 533 671c ++

Example in Compound at IC50 of hTHP-1 (uM) 534 671b + 535 671a > 30 536 605d > 30 537 605b +++ 538 643a + 539 643b + 540 171c ++ 541 171b + 542 171a > 30 543 1 734 +++ 545 736 ++ 546 735 ++ 547 721c ++++ 548 720c +++ 549 723c +++ 550 729 +++ 553 723b ++++ 554 723a + 555 721b ++++ 556 721a + 557 720b + 558 720a +++ 559 729b ++++ 560 729a + 601a +++ 601b + 602a > 30,0000 602b ++ 604a + 604b +++ 608a +++

Example in the Compound in the IC50 of hTHP-1 (uM) 608b + 608c +++ 608d ++ 706 > 30.0000 707 > 30.0000 708 > 30.0000 709 > 30.0000 710 > 30.0000 711 > 30, 0000 712 > 30.0000 713 ++ 716a ++++ 716b +++ 717 +++ 718a ++++ 719 +++ 722 ++ 724 +++ 725a ++ 726 ++ 726a > 30.0000 726b +++ 727 +++ 727a ++ 727b ++++ 728 ++ 728a + 728b +++ 730 + 730a + 730b ++ 731 ++

Example in Compound in IC50 of hTHP-1 (uM) 731a + 731b +++ 733 ++ 737 +++ 738 > 30.0000 Table B3 Example in IC50 (μM) 561 +++ 562 +++ 563 + 564 + + 565 + 566 +++ 567 + 568 ++++ 569 +++ 570 +++ 571 ++ 572 ++ 573 ++ 574 ++ 575 ++ 576 +++ 577 ++ 578 ++ 579 ++ 580 ++ 581 > 30 582 ++++ 583 ++ 584 > 30 585 ++

Example in IC50 (μM) 586 +++ 587 + 588 ++ 589 ++ 590 ++ 591 ++ 592 > 30 593 > 30 594 ++ 595 ++ 596 ++ 597 ++++ 598 +++ 599 + + 600 +++ 601 + 602 +++++ 603 ++ 604 ++++ 605 +++ 606 > 30 607 +++ 608 ++++ 609 +++ 610 +++ 611 ++ 612 + + 613 > 30 614 > 30 615 +++ 616 +++ 617 +

Example in IC50 (μM) 618 ++++ 619 ++ 620 +++ 621 ++++ 622 ++ 623 +++ 624 +++ 625 ++ 626 +++ 627 +++ 628 ++++ 629 +++ 630 + 631 ++ 632 ++ 633 + 634 ++ 635 > 30 636 > 30 637 +++ 638 +++++ 639 +++ 640 + 641 ++ 642 > 30 643 ++ 644 > 30 645 + 646 ++++ 647 +++ 648 + 649 ++++

Example in IC50 (μM) 650 ++ 651 ++++ 652 + 653 ++++ 654 + 655 > 30 656 ++ 657 ++ 658 > 30 659 +++ 660 + 661 ++ 662 + 663 +++ + 664 ++++ 665 +++ 666 + 667 ++ 668 > 30 669 +++++ 670 ++ 671 +++++ 672 ++ 673 + 674 +++ 675 + 676 +++ 677 + 678 +++++ 679 ++++ 680 + 681 ++++

Example in IC50 (μM) 682 ++ 683 ++ 684 > 30 685 +++ 686 > 30 687 +++ 688 + 689 ++ 690 > 30 691 +++ 692 + 693 ++ 694 > 30 695 ++ 696 + 697 ++++ 698 ++ 699 +++ 700 + 701 + 702 > 30 703 ++ 704 +++ 705 + 706 +++ 707 +++++ 708 + 709 ++ 710 + 711 +++ + 712 + 713 ++++

Example in IC50 (μM) 714 ++ 715 ++++++ 716 ++ 717 ++ 718 > 30 719 ++ 720 ~30 721 ++++ 722 ++ 723 ++ 724 > 30 725 > 30 726 + ++ 727 ++++ 728 ++ Compound 984a + Compound 984b ++++ Compound 983 ++++ Compound 985a ++ Compound 985b +++ Table B4 Example in IC50 of hTHP-1 729 ++ 730 +++ 731 ++++ 732 ++ 733 ++++ 734 +++ 735 +++ 736 +++ 737 +++ 738 ++

Example in IC50 of hTHP-1 739 +++++ 740 ++++ 741 ++++ 742 +++++ 743 ++ 744 ++++ 745 ++ 746 +++++ 747 +++ ++ 748 +++ 749 ++ 750 +++ 751 ++ 752 ++ 753 +++ 754 ++ 755 +++ 756 + 757 +++++ 758 ++ 759 +++ 760 >30 761 + +++ 762 + 763 +++ 764 + 765 +++++ 766 ++ 767 +++++ 768 +++ 769 + 770 ++++

Example in IC50 of hTHP-1 771 +++ 772 + 773 ++++ 774 + 775 ++++ 776 + 777 +++ 778 ++ 779 +++++ 780 +++ 781 +++++ 782 +++ 783 ++ 784 + 785 ++++ 786 + 787 +++++ 788 ++ 789 ++++ 790 + 791 +++ 792 >30 793 +++ 794 + Table B5. Example on IC50 of hTHP-1 in 2% IC50 of hTHP-1 in FBS 10% FBS 795 ++++ 796 +++++ +++ 797 +++++ +++++ 798 ++++ ++++ 799 +++ ND

Example on IC50 of hTHP-1 in 2% IC50 of hTHP-1 in FBS 10% FBS 800 ND + 801 ND ++++ 802 ND +++ 803 ND ++++ 804 ND ++++ 805 ND ++ ++ 806 ND +++++ 807 ND ++++ 808 ND +++++ 809 ND ++++ 810 ND ND 811 ND ++++ 812 ND ++++ 813 +++++ + ++++ 814 ++ ++ 815 ++++ +++++ 816 + ++ 817 + ++ 818 +++ ++++ 819 + + 820 >30 µM >30 µM 821 ++++ ND 822 ++ 823 ++ 824 ND +++ 825 ND +++++ 826 ND ++++ 827 ND ++ 828 ND + 829 ND ++ 830 ND ++++

Example on IC50 of hTHP-1 in 2% IC50 of hTHP-1 in FBS 10% FBS 831 ND ++ 832 ND ++++ 833 ND ++ 834 ND ++++ 835 ND +++ 836 ND +++ 837 ND +++++ 838 ND ++++ 839 ND ++ 840 ND ++++ 841 ND ++ 842 ND +++++ 843 ND +++ 844 ND +++ 845 ND ++++ ++ 846 ND +++ 847 ND + 848 ND +++++ 849 ND ++ 850 ND +++++ 851 ND +++ 852 ND + 853 ND +++++ Table B6. Example on IC50 of hTHP-1 in 10% FBS 854 ++++ 855 +++++ 856 ++++ 857 ++++ 858 ++++ 861 ++++ 863 ++++

Example on IC50 of hTHP-1 in 10% FBS 864 +++ 865 ++++ 866 ++++ 867 ++++++ 868 +++ 869 +++++ 870 ++ Study Example 1 .

[002652] The CARD8 gene is located within the inflammatory bowel disease (IBD) binding region 6 on chromosome 19. CARD8 interacts with NLRP3, and apoptosis-associated Speck-like protein to form a caspase-1 activation complex called undermined the NLRP3 inflammasome. The NLRP3 inflammasome mediates the production and secretion of interleukin-1β, processing pro-IL-1β into mature secreted IL-1β. In addition to its role in the inflammasome, CARD8 is also a potent inhibitor of nuclear factor NF-κB. Activation of NF-κB is essential for the production of pro-IL-1. Since overproduction of IL-1β and dysregulation of NF-κB are hallmarks of Crohn's disease, CARD8 is considered here to be a risk gene for inflammatory bowel disease. A significant association of CARD8 with Crohn's disease was detected in two UK studies with a risk effect for the secondary allele of the single nucleotide polymorphism (SNP) not synonymous with a C allele at rs2043211. This SNP introduces a premature stop codon, resulting in the expression of a severely truncated protein. The CARD8 variant protein lacks the ability to suppress NF-κB activity, which results in constitutive production of pro-IL-1β, which is a substrate for the NLRP3 inflammasome. A gain-of-function mutation in an NLRP3 gene (e.g., any of the gain-of-function mutations described in this paper, e.g., any of the gain-of-function mutations in an NLRP3 gene) is believed to described herein) combined with a loss-of-function mutation in a CARD8 gene (e.g., a C allele at rs2043211) results in the development of diseases related to increased NLRP3 inflammasome expression and/or activity. Patients with, for example, a gain-of-function mutation in an NLRP3 gene and/or a loss-of-function mutation in a CARD8 gene are predicted to show improved therapeutic response to treatment with an NLRP3 antagonist.

[002653] A study is designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy specimens from patients with Crohn's disease or ulcerative colitis; and whether specific genetic variants identify patients with Crohn's disease or ulcerative colitis who are more likely to respond to treatment with an NLRP3 antagonist.

[002654] The secondary objectives of this study are to: determine whether an NLRP3 antagonist reduces inflammasome activity in Crohn's disease and ulcerative biopsy samples (which compare Crohn's disease and ulcerative colitis results with control patient results ); to determine whether an NLRP3 antagonist reduced inflammatory cytokine protein and RNA expression in Crohn's disease and ulcerative colitis samples; to determine whether baseline RNA levels (without ex vivo treatment) of NLRP3, ASC and IL-1β are higher in biopsy samples from patients with a situation of resistance to the anti-TNFα agent; and stratify the results according to the presence of specific genetic mutations in genes encoding ATG16L1, NLRP3, and CARD8 (eg, any of the mutations in the ATG16L1 gene, NLRP3 gene, and CARD8 gene described herein). Methods  Baseline RNA expression assessment of

NLRP3 and inhibition of quantification of inflammasome activity by an NLRP3 antagonist in diseased tissue biopsies from patients with Crohn's disease and ulcerative colitis.  To determine whether NLRP3 antagonist treatment reduces the inflammatory response in disease biopsies from patients with Crohn's disease based on decreased RNA expression of the inflammatory gene measured with Nanostring.  Sequence patient DNA to detect specific genetic mutations in the ATG16L1 gene, NLRP3 gene, and CARD8 gene (e.g., any of the exemplary mutations in these genes described herein) and then stratify the results of functional assays according to the presence of these genetic mutations.

Experimental Design  Human subjects and tissue: Endoscopic or surgical biopsies of diseased areas in patients with Crohn's disease and ulcerative colitis who are naive to anti-TNFα treatment or resistant to anti-TNFα treatment; additionally, biopsies from control patients (surveillance colonoscopy or areas free of inflammation from patients with colorectal cancer) are studied.  Ex vivo Treatment Model: Organ culture or LPMC, as determined appropriate  End points to be measured: Before ex vivo treatment -- NLRP3 RNA level After ex vivo treatment - inflammasome activity (whether IL-1β processed , processed caspase-1 or secreted IL-1β); RNA for inflammatory cytokines (Nanostring); viable T cell number and/or T cell apoptosis.

 Data Analysis Plan:  Determine whether NLRP3 antagonist treatment decreases processed IL-1β, processed caspase-1 or secreted IL-1β and inflammatory cytokine RNA levels.  Stratify response data according to biopsy treatment situation and the presence of gene mutations in the NLRP3 gene, CARD8 gene, and ATG16L1 gene (eg, any of the exemplary gene mutations of these genes described in this document). Study Example 2. Treatment of anti-TNFα resistant patients with NLRP3 antagonists

[002655] PLoS One, Nov 24, 2009;4(11):e7984 describes that mucosal biopsies were obtained at endoscopy in actively inflamed mucosa from patients with Ulcerative Colitis refractory to corticosteroids and/or immunosuppression, before and 4 at 6 weeks after their first infliximab infusion (an anti-TNFα agent) and in normal mucosa of control patients. Patients in this study were classified for response to infliximab based on endoscopic and histological findings at 4 to 6 weeks after the first infliximab treatment as responders or non-responders. The transcriptomic RNA expression levels of these biopsies were accessed by the inventors of the invention disclosed herein from GSE 16879, the publicly available Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo /geo2r/?acc=GSE16879). Expression levels of RNA encoding NLRP3 and IL-1β were determined using GEO2R (a tool available on the same website), based on probe sets 207075_at and 205067_at, respectively. Surprisingly, Crohn's disease patients who are unresponsive to infliximab (an anti-TNFα agent) were found to have higher NLRP3 and IL-1β RNA expression than responsive patients (Figures 1 and 2). Surprisingly similar results of superior NLRP3 and IL-1β RNA expression in patients with UC who are unresponsive to infliximab (an anti-TNFα agent) compared to patients responsive to infliximab (an anti-TNFα agent) (Figures 3 and 4) were found.

[002656] It is hypothesized, in the present document, that said higher levels of RNA expression levels of NLRP3 and IL-1β in anti-TNFα agent non-responders, result in the activation of NLRP3 which, by in turn, it results in the release of IL-1β that induces the production of IL-23, which results in said resistance to anti-TNFα agents. Therefore, treatment of anti-TNFα non-responders with Crohn's disease and UC with an NLRP3 antagonist would prevent this cascade and thus prevent the development of non-responsiveness to anti-TNFα agents. Indeed, resistance to anti-TNFα agents is common in other inflammatory or autoimmune diseases. Therefore, the use of an NLRP3 antagonist for the treatment of inflammatory or autoimmune diseases will block the mechanism that results in non-responsiveness to anti-TNFα agents. Consequently, the use of NLRP3 antagonists will increase the sensitivity of patients with inflammatory or autoimmune diseases to anti-TNFα agents, which results in a reduced dose of anti-TNFα agents for the treatment of these diseases. Therefore, a combination of an NLRP3 antagonist and an anti-TNFα agent can be used in the treatment of diseases where TNFα is overexposed, such as inflammatory or autoimmune diseases, to prevent such unresponsive development of patients to anti-TNFα agents. Preferably, this combination treatment can be used in the treatment of IBD, eg Crohn's disease and UC.

[002657] Furthermore, the use of NLRP3 antagonists offers an alternative to anti-TNFα agents for the treatment of diseases in which TNFα is overexposed. Therefore, NLRP3 antagonists offer an alternative to inflammatory or autoimmune diseases from anti-TNFα agents such as IBD (eg Crohn's disease and UC).

[002658] Systemic anti-TNFα agents are also known to increase the risk of infection. Gastrointestinal-restricted NLRP3 antagonists, however, offer a treatment that targets the gastrointestinal tract (ie, non-systemic treatment), preventing such infections. Therefore, treatment of TNFα intestinal diseases, such as IBD (i.e., Crohn's disease and UC), with gut-restricted NLRP3 antagonists has the added advantage of reducing the risk of infection compared with anti-inflammatory agents. -TNFα. Proposed Experiment:

[002659] To determine the expression of NLRP3 and caspase-1 in LPMCs and epithelial cells in patients with non-active disease, in patients with active disease, in patients with active corticosteroid-resistant disease, in patients with active disease resistant to blocking agents of TNF. The expression of NLRP3 and caspase-1 in LPMCs and epithelial cells will be analyzed by RNAScope technology. The expression of active NLRP3 signature genes will be analyzed by Nanostring technology. A pilot analysis to determine viability will be performed with 5 control samples, 5 samples of active CD lesions and 5 samples of active UC lesions. Study example 3.

[002660] NLRP3 antagonists are shown to reverse resistance to anti-TNF-induced T cell deletion/apoptosis in biopsy specimens from patients with IBD whose disease is clinically considered resistant or unresponsive to anti-TNF therapy.

[002661] A study is designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy specimens from patients with Crohn's disease or ulcerative colitis; and whether an NLRP3 antagonist will synergize with anti-TNFα therapy in patients with Crohn's disease or ulcerative colitis.

[002662] The secondary objectives of this study are: to determine whether an NLRP3 antagonist reduces inflammasome activity in Crohn's disease and ulcerative biopsy samples (which compares Crohn's disease and ulcerative colitis results with control patient results); to determine whether an NLRP3 antagonist reduced inflammatory cytokine protein and RNA expression in Crohn's disease and ulcerative colitis samples; to determine whether an NLRP3 antagonist in the absence of anti-TNFα antibody co-treatment induces T cell exclusion in Crohn's disease and ulcerative colitis biopsy specimens; and to determine whether baseline RNA levels (without ex vivo treatment) of NLRP3, ASC and IL-1β are higher in biopsy samples from patients with anti-TNFα agent resistance situation. Methods  Evaluation of baseline NLRP3 RNA expression and inhibition of quantification of inflammasome activity by an NLRP3 antagonist in diseased tissue biopsies from patients with Crohn's disease and ulcerative colitis.  Determining whether there is synergy between an NLRP3 antagonist and anti-TNF antibody with respect to effects on T cell exclusion/apoptosis in disease biopsies from patients with Crohn's disease and ulcerative colitis.  To determine whether NLRP3 antagonist treatment reduces the inflammatory response in disease biopsies from patients with Crohn's disease based on decreased RNA expression of the inflammatory gene measured with Nanostring. Experimental Project

 Human subjects and tissue: Endoscopic or surgical biopsies of diseased areas in patients with Crohn's disease and ulcerative colitis who are naive to anti-TNFα treatment or resistant to anti-TNFα treatment; additionally, biopsies from control patients (surveillance colonoscopy or areas free of inflammation from patients with colorectal cancer) are studied.  Ex vivo Treatment Model: Organ culture or LPMC, as determined appropriate  Ex vivo treatments: NLRP3 antagonist (2 concentrations), negative control (vehicle), positive control (caspase-1 inhibitor) each in the presence - the presence or absence of anti-TNF antibody at an appropriate concentration to distinguish differences in apoptotic T cell between biopsies of patients with Crohn's disease resistant to anti-TNF and sensitive to anti-TNF.

Each treatment condition is evaluated on at least duplicate samples.  End points to be measured: Before ex vivo treatment -- NLRP3 RNA level After ex vivo treatment - inflammasome activity (either processed IL-1-1β, processed caspase-1 or secreted IL-1-1β); RNA for inflammatory cytokines (Nanostring); viable T cell number and/or T cell apoptosis.  Data Analysis Plan:  To determine whether NLRP3 antagonist co-treatment increases T cell apoptosis/deletion in response to anti-TNF.  To determine whether the level of NLRP3 RNA expression is higher in samples of Crohn's disease and ulcerative colitis resistant to TNF compared to samples naive to anti-inflammatory treatment.

TNF.  To determine whether NLRP3 antagonist treatment decreases processed IL-1-1β, processed caspase-1 or secreted IL-1β and inflammatory cytokine RNA levels. Biological Assay - Nigericin-stimulated IL-1β secretion assay in THP-1 cells

[002663] Monocytic THP-1 cells (ATCC: TIB-202) were maintained according to the supplier's instructions in RPMI media (RPMI/Hepes +10% fetal bovine serum + Sodium pyruvate + 0.05 mM of Beta-mercaptoethanol (1000x stock) + Pen-Strep). Cells were volume differentiated with 0.5 µM phorbol 12-myristate 13-acetate (PMA; Sigma # P8139) for 3 hours, the medium was changed, and the cells were plated at 50,000 cells per well in 384-well flat-bottomed cell culture plates (Greiner, # 781986), and allowed to differentiate overnight. Compound in a 1:3.16 serial dilution in DMSO was added 1:100 to the cells and incubated for 1 hour. The NLRP3 inflammasome was activated with the addition of 15 µM (final concentration) of Nigericin (Enzo Life Sciences, no. BML-CA421-0005), and the cells were incubated for 3 hours. 10 µl of supernatant was removed and IL-1β levels were monitored using an HTRF assay (CisBio, #62IL1PEC) according to the manufacturer's instructions. Viability and pyroptosis were monitored by adding PrestoBlue Cell Viability Reagent (Life Technologies, # A13261) directly into the cell culture plate.

[002664] Several embodiments of the invention have been described. However, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Consequently, other deployments are within the scope of the claims presented below.

Claims (396)

1. Compound, characterized by the fact that it has the Formula AA R3 (R6)o HN O O (R7)p 1 S B (R )m A N N H(R2)n Formula AA wherein m = 0, 1 or 2; n = 0, 1 or 2; o = 1 or 2; p = 0, 1, 2 or 3; wherein the sum of o and p is 1 to 4; wherein A is a 5- to 10-membered heteroaryl or a C6-C10 aryl; B is a 6-membered heteroaromatic ring containing 1 to 3 N atoms or an N-oxide thereof; wherein at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA; R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5 , SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl , 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl a, OCO(5 to 10 membered heteroaryl) and OCO(3 to 7 membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy , -O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connected thereto, independently form at least one C4-C12 monocyclic or bicyclic carbocyclic ring or at least one monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein: a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl , C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl , 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1- C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl , wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more of hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) and NHCO(3 to 7 membered heterocycloalkyl) are optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, NH, NR13 and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl , C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C=NR13)NR11R12, S(O2)C1- C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted by one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl or NR11R12; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached, wherein the ring is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R13 is C1-C6 alkyl, C1-C6 haloalkyl or -(Z1-Z2)a1-Z3; each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl and -(Z1-Z2)a1-Z3; a1 is an integer selected from 0 to 10 (eg 0 to 5); each Z1 is independently C1-C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; each Z2 is independently a bond, NH, N(C1-C6 alkyl), -O-, -S- or 5- to 10-membered heteroarylene; Z3 is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with a or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R3 is selected from hydrogen, cyano, hydroxy, CO2Cl- C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl, wherein the C1-C2 alkylene group is optionally substituted by oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or monocyclic or bicyclic C6-C10 aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted by 1 or 2 R6; R15 is -(Z4-Z5)a2-Z6; a2 is an integer selected from 1 to 10 (eg 1 to 5 (eg 2 to 5)); each Z4 is independently selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-; provided that the Z4 group bonded directly to R1 or R2 is -O- or -S-; each Z5 is independently C1 -C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; and Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy) or an optionally substituted group selected from the group consisting of: C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each one of which is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) ) and hydroxy; provided that the compound of Formula AA is not a compound selected from the group consisting of: , , HN H N N Y Y N The O HO , F , H2N H H N N H2N N No O S N O S N O O O O HO HO , and H2N H N N Y Y N The O HOF; or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, characterized in that A is a 5-membered heteroaryl. 3. Compound according to claim 1, characterized in that A is a heteroaryl with 6 to 10 members. 4. Compound according to claim 1, characterized in that A is a C6-C10 aryl. 5. Compound according to claim 1 or 2, characterized in that A is a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH and NR1. 6. A compound according to claim 1 or 2, characterized in that A is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, in which the heteroatom is not attached to the heteroaryl position which is linked to the chemical moiety S(O)(NHR3)=N. 7. Compound according to any one of claims 1 or 2 and 6, characterized in that A is thiophenyl. 8. A compound according to claim 1 or 2, characterized in that A is thiazolyl. 9. A compound according to claim 1 or 2, characterized in that A is pyrazolyl. 10. Compound according to any one of claims 1 and 4, characterized in that A is phenyl. 11. Compound according to any one of claims 1 to 10, characterized in that m=1 and n=0. Compound according to any one of claims 1 or 2, 8 and 11, characterized in that the optionally substituted ring A is . 13. Compound according to any one of claims 1 or 2, 8 and 11, characterized in that the optional ring - R1 N mind substituted A is S. Compound according to any one of claims 1 or 2, 8 and 11, characterized in that the optionally substituted ring A is . 15. Compound according to any one of claims 1 or 2, 8 and 11, characterized in that the optional ring S R1 N mind substituted A is . A compound according to any one of claims 1 or 2, 9 and 11, characterized in that the optionally substituted ring A is or (for example, ). A compound according to any one of claims 1 or 2 and 11, characterized in that the optionally substituted ring A is . A compound according to any one of claims 1 or 2 and 11, characterized in that the optionally substituted ring A is . A compound according to any one of claims 1, 4 and 11, characterized in that the optionally substituted ring A is . 20. Compound according to any one of claims 1 to 10, characterized in that m=1 and n=1. Compound according to any one of claims 1 or 2, 8 and 20, characterized in that the optionally substituted ring A is . Compound according to any one of claims 1 or 2, 9 and 20, characterized in that the optionally substituted ring A is . 23. Compound according to any one of claims 1 or 2, 9 and 20, characterized in that the optional ring mind replaced A is . Compound according to any one of claims 1 or 2, 9 and 20, characterized in that the optionally substituted ring A is . Compound according to any one of claims 1 or 2, 8 and 20, characterized in that the optionally substituted ring A is . A compound according to any one of claims 1, 2, 7 and 20, characterized in that the optionally substituted ring A is . A compound according to any one of claims 1, 2, 7 and 20, characterized in that the optionally substituted ring A is . Compound according to any one of claims 1, 4, 10 and 20, characterized in that the optionally substituted ring A is . 29. Compound according to any one of claims 1 to 28, characterized in that R1, when present, is in- independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. A compound according to any one of claims 1 to 29, characterized in that R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, halo or NR8R9. A compound according to any one of claims 1 to 29, characterized in that R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1- (dimethylamino)ethyl; fluorine; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. A compound according to any one of claims 1 to 28, characterized in that R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluorine. A compound according to any one of claims 1 to 28 and 32, characterized in that R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. 34. Compound according to any one of claims 1 to 28 and 32, characterized in that R1 is fluorine. A compound according to any one of claims 1 to 34, characterized in that R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. A compound according to any one of claims 1 to 34, characterized in that R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo or NR8R9. A compound according to any one of claims 1 to 34, characterized in that R2 , when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluorine; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 38. A compound according to any one of claims 1 to 34, characterized in that R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluorine. 39. Compound according to any one of claims 1 to 10, 20, 22 to 25 and 27, characterized in that R1 and R2 are on adjacent atoms and, considered together with the atoms that connect them , independently form a C4-C12 monocyclic or bicyclic carbocyclic ring (e.g. C5 or C6 carbocyclic ring) or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom carbon, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or independently selected heteroatomic groups. none of O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O ) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g. methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g. isopropoxy), OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl) and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, the C3-C10 cycl 3- to 10-membered alkyl and heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo (e.g., fluorine), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g. amino, methylamino or dimethylamino), =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 40. Compound according to any one of claims 1 to 10, 20, 22 to 23, 25 and 27, characterized in that R1 and R2 are on adjacent atoms and, considered together with atoms connecting the themselves independently form a monocyclic or bicyclic C5-C6 carbocyclic ring optionally independently substituted by one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein methyl, isopropoxy , azetidinyl and oxetanyl are optionally substituted by one or more substituents, each independently selected from hydroxy, fluorine, amino, methylamino and dimethylamino; or R1 and R2 are on adjacent atoms and, taken together, independently form: , , or , each optionally substituted by one or more substituents independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, in that methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluorine, amino, methylamino and dimethylamino; wherein the asterisk represents a point of attachment to a carbon atom; and o represents a point of attachment to a carbon or a nitrogen atom. 41. Compound according to any one of claims 1 to 10, 20, 22 to 23, 25 and 27, characterized in that R1 and R2 are on adjacent atoms and, considered together with the atoms connecting them , independently form at least one C4-C12 bicyclic spirocyclic carbocyclic ring, wherein the carbocyclic ring is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, in that methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents, each independently selected from hydroxy, fluorine, amino, methylamino and dimethylamino. Compound according to any one of claims 1 to 10, 20, 22 to 23, 25 and 27, characterized in that R1 and R2 are on adjacent atoms and, considered together with the atoms connecting them , independently form at least one bicyclic spirocyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S , S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluorine, amino, methylamino and dimethylamino. A compound according to any one of claims 1 or 2 and 8, characterized in that A is thiazolyl (eg 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted by hydroxy (e.g. 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted by hydroxy (e.g., methyl, hydroxymethyl or hydroxyethyl). A compound according to any one of claims 1 or 2 and 9, characterized in that A is pyrazolyl (eg 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted by 1 to 3 halo (e.g. fluorine). 45. Compound according to claim 1, characterized by the fact that A is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted by NR8R9 (e.g. dimethylamino); and R2, when present, is halo (e.g., fluorine). 46. Compound according to any one of claims 1 or 2 and 7, characterized in that A is thiophenyl (eg 2-thiophenyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. isopropyl, 2-hydroxy-2-propyl or 1-propanoyl). A compound according to any one of claims 1 or 2, characterized in that the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not attached to the position of the heteroaryl that is attached to the chemical moiety S(O)(NHR3)=N; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O) two; and b) when one or both adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein a C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 , =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. A compound according to any one of claims 1 to 2, 9 and 47, characterized in that the optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2; and b) when one or both adjacent atoms are a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring and the heterocyclic ring are optionally substituted independently by one or more substituents, each independently - carefully selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S (O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with a or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. A compound according to any one of claims 1 or 2 and 47, characterized in that the optionally substituted ring A is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or the heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1- C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1 -C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, the C3-C10 cyclo- 3- to 10-membered alkyl and heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1 -C6 alkoxy, oxo, NR8R9, =NR10, CO-OC1-C6 alkyl, C6-C10 aryl and CONR8R9. A compound according to any one of claims 1 or 2 and 7, characterized in that the optionally substituted ring A is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and /or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2) C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2) C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. A compound according to any one of claims 1 or 2 and 9, characterized in that the optionally substituted ring A is , wherein Rx is selected from the group consisting of H and C1-C6 alkyl (for example methyl); Z1 is selected from the group consisting of O, NH and -CH2- optionally substituted by 1 to 2 R20; Z2 is selected from the group consisting of NH and -CH2- optionally substituted by 1-2 R20; Z3 is selected from the group consisting of -CH2- optionally substituted by 1 to 2 R20, -CH2CH2- optionally substituted by 1-2 R20, and -CH2CH2CH2- optionally substituted by 1-2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g. fluorine), oxo, C1-C6 alkyl (e.g. methyl or ethyl) optionally substituted by an R21, C1-C6 alkoxy (e.g. , methoxy, ethoxy or isopropoxy) optionally substituted by an R21, NR8R9, 3 to 10 membered heterocycloalkyl (e.g. azetidinyl or pyrrolidinyl) optionally substituted by an R21 or a pair of R20 on the same atom taken together with the connecting atom they independently form a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted by OS(O)2Ph; R21 is selected from the group consisting of halo (eg fluorine), NR8R9, C2-C6 alkynyl (eg ethynyl) and C1-C6 alkoxy (eg methoxy); R8 and R9 at each occurrence are independently selected from hydrogen, C1-C6 alkyl (eg methyl or ethyl), COR13 and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (eg methyl or t-butyl) and C1-C6 haloalkyl (eg trifluoromethyl). A compound according to any one of claims 1 or 2 and 9, characterized in that the optionally substituted ring A is , wherein Z4 is selected from the group consisting of -CH2-, -C(O )- and NH; Z5 is selected from the group consisting of O, NH, N-CH3 and -CH2-. A compound according to any one of claims 1 to 52, characterized in that B is pyridyl or an N-oxide thereof. 54. Compound according to any one of claims 1 to 53, characterized in that B is 3-pyridyl. 55. Compound according to any one of claims 1 to 54, characterized in that o=2 and p=1. A compound according to any one of claims 1 to 55, characterized in that the substituted ring B is N R6 R7 R6 . 57. A compound according to any one of claims 1 to 56, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl , C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1 -C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO (4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 58. A compound according to any one of claims 1 to 57, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl and C6- C10 aryl. 59. Compound according to any one of claims 1 to 58, characterized in that each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 60. A compound according to any one of claims 1 to 59, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl , C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1 -C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO (4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 61. Compound according to any one of claims 1 to 60, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3- C7 cycloalkyl, halo and C6-C10 aryl. 62. Compound according to any one of claims 1 to 61, characterized in that each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. A compound according to any one of claims 1 to 53, characterized in that the substituted ring B is 4-pyridyl. 64. Compound according to any one of claims 1 to 53 and 63, characterized in that o=2 and p=0. 65. Compound according to any one of claims 1 to 53 and 63 to 64, characterized in that the substituent ring R6 N of B is R6. 66. Compound according to any one of claims 1 to 53 and 63 to 65, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5 to 5-membered heteroaryl 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) members), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. A compound according to any one of claims 1 to 53 and 63 to 66, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl. 68. Compound according to any one of claims 1 to 53 and 63 to 67, characterized in that each R6 is isopropyl. 69. Compound according to any one of claims 1 to 53 and 63, characterized in that o=2 and p=2. 70. Compound according to any one of claims 1 to 53, 63 and 69, characterized in that the substituted ring R7 R6 N R7 Be R6 . A compound according to any one of claims 1 to 53, 63 and 69 to 70, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4-6 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. A compound according to any one of claims 1 to 53, 63 and 69 to 71, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6 -C10 aryl. A compound according to any one of claims 1 to 53, 63 and 69 to 72, characterized in that each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. A compound according to any one of claims 1 to 53, 63 and 69 to 73, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4-6 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. A compound according to any one of claims 1 to 53, 63 and 69 to 74, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6 -C10 aryl. 76. A compound according to any one of claims tions 1 to 53, 63 and 69 to 75, characterized in that each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 77. Compound according to any one of claims 1 to 53, 63 and 69 to 76, characterized in that a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13 and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 78. Compound according to any one of claims 1 to 53, 63 and 69 to 76, characterized in that a pair of R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 79. A compound according to claim 77 or 78, characterized in that the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted by one or more oxo, CH3 or hydroxy. 80. Compound according to claim 79, characterized in that the C5 carbocyclic ring is replaced by a CH3. 81. Compound according to claim 79, characterized by the fact that the C5 carbocyclic ring is geminally substituted by two CH3. 82. A compound according to claim 77 or 78, characterized in that the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring. 83. A compound according to any one of claims 1 and 43 to 52, characterized in that the substituted ring B is (Y)q N(Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring. 84. A compound according to any one of claims 1 and 43 to 52, characterized in that the substituted ring B is (Y)q N(R7)p; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring. 85. Compound according to any one of claims 1 and 43 to 52, characterized in that the substituted ring B is R6 N R6(R7)p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluorine); p is 0 or 1. 86. Compound according to any one of claims 1 and 43 to 52, characterized in that the substituted ring B is R6 N 7 R6 (R )p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluorine); p is 0 or 1. 87. A compound according to any one of claims 1 and 43 to 52, characterized in that the substituted ring B is (Y)q N R6 R7 ; R6 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl) and C3-C10 cycloalkyl (eg cyclopropyl); R7 is selected from C1-C6 alkyl (for example methyl, ethyl or isopropyl), C1-C6 haloalkyl (for example trifluoromethyl) and C3-C10 cycloalkyl (for example cyclopropyl or cyclobutyl); or R6 and R7, considered together with the atoms that connect them, regardless pendently form a C5 carbocyclic ring optionally substituted by one or more C1-C6 alkyl (e.g. methyl); q is 0, 1 or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring. 88. Compound, characterized by the fact that it has the Formula AA R3 (R6)o HN O O (R7)p 1 S B (R )m A N N H (R2)n Formula AA wherein the compound of Formula AA is selected from R3 (R6'' )o HN O O (R7)p 1 B (R )m S A' N N H (R2)n (Formula AA-1), R3 (R 6)o HN O O (R 7)p 1 B (R )m' S A'' N N H(R2)n' (Formula AA-2), R3(R6)o HN O O (R7)p 1' B (R )m'' S A'' N N H (R2')n'' (Formula AA-3), R3 (R6) o HN O O (R7)p 1 B' (R )m''' S A'' N N H (R2'')n''' (Formula AA-4) and (R6' )o H 2N O O (R 7') p 1 B'' (R ) m''' S S N N H (R 2'') n''' (Formula AA-5), wherein m = 0, 1 or 2; n = 0, 1 or 2; m' = 0, 1 or 2; n' = 0, 1 or 2; wherein the sum of m' and n' is 0, 1 or 3; m'' = 0, 1 or 2; n'' = 0, 1 or 2; where the sum of m'' and n'' is 2; m''' = 1; n''' = 1; o = 1 or 2; p = 0, 1, 2 or 3; wherein the sum of o and p is 1 to 4; wherein A' is selected from: a 6- to 10-membered heteroaryl, a C6-C10 aryl, a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)=N; A'' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)=N; B is a 6-membered heteroaromatic ring containing 1 to 3 N atoms or an N-oxide thereof; B' is 2-pyridyl, 3-pyridyl or an N-oxide thereof; B'' is 4-pyridyl or an N-oxide thereof; wherein at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-2, Formula AA-3 and Formula AA-4; at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-5; at least one R6 is ortho to the bond connecting ring B to the NHC(O) group of Formula AA-1; R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5 , SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl , 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl a, OCO(5 to 10 membered heteroaryl) and OCO(3 to 7 membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy , -O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; or a pair of R1 and R2 on adjacent atoms, taken together with the atoms connected thereto, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein: a ) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 ; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S( O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents. tes, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S( O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S( O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently se- chosen from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R1' and R2' are each independently selected from C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl, Br, I, CN, NO2, CO2C1-C6 alkyl, CO2C3- C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NR8R9, C(O )R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein C2-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 to 7 membered, C6-C10 aryl, 5-10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C 10 aryl, OCO(5 to 10 membered heteroaryl) and OCO(3 to 7 membered heterocycloalkyl); where each C1-C6 alkyl substituent and each substituent C1-C6 alkoxy of the R1' or R2' C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally substituted independently by one to three hydroxy, -O(C0-C3 alkylene) C6-C10 aryl, halo, NR8R9 or oxo; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R1' and R2' on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1 -C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, the C3-C10 cycloalkyl, and the heterocyl 3- to 10-membered chloroalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R2'' is F or CH3; or when the compound of Formula AA is a compound of Formula AA-4, a pair of R1' and R2' on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C12 monocyclic or bicyclic carbocyclic ring or a heterocyclic ring with 5 a 12-membered monocyclic or bicyclic compound that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-membered heterocycloalkyl 10-membered and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, the C3-C10 cycloalkyl and the 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1- C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl , wherein R6 and R7 are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl , CONR8R9, 3 to 7 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(3 to 7 membered heterocycloalkyl ), C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy by which R6 or R7 is substituted is optionally substituted by one or more of hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a ring carbocyclic or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hy- droxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6 and R7 are each independently selected from C1-C6 unbranched alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1 -C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl and C2-C6 alkenyl, wherein R6' and R7' are each optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, heterocycloalkyl with 3 to 7 membered, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy by which R6' or R7' is substituted is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6' or R7' is optionally fused to a carbocyclic ring or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6' and R7' on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more independently selected substituents among hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R6'' is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(3-7 membered heterocycloalkyl), C6-C10 aryl, 5-10 membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl )2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6" is optionally substituted by one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5-membered heteroaryl 10-membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and in that the C1-C6 alkyl or C1-C6 alkoxy by which R6" is replaced is optionally substituted by one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6" is optionally fused to a carbocyclic ring or a five to seven membered heterocyclic ring containing one or two heteroatoms independently selected from oxygen , sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, the C6-C10 aryl and the 5-10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl and OC1-C6 alkyl; or a pair of R6'' and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from among O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9; R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C=NR13)NR11R12, S(O2)C1- C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted by one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR11R12; or R8 and R9, taken together with the nitrogen to which they are attached, form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen to which they are attached, wherein the ring is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R13 is C1-C6 alkyl, C1-C6 haloalkyl or -(Z1-Z2)a1-Z3; each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl and -(Z1-Z2)a1-Z3; a1 is an integer selected from 0 to 10 (eg 0 to 5); each Z1 is independently C1-C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; each Z2 is independently a bond, NH, N(C1-C6 alkyl), -O-, -S- or 5- to 10-membered heteroarylene; Z3 is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with a or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; R3 is selected from hydrogen, cyano, hydroxy, CO2Cl- C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl, wherein the C1-C2 alkylene group is optionally substituted by oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or monocyclic or bicyclic C6-C10 aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted by 1 or 2 R6; R15 is -(Z4-Z5)a2-Z6; a2 is an integer selected from 1 to 10 (eg 1 to 5 (eg 2 to 5)); each Z4 is independently selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-; provided that the Z4 group bonded directly to R1 or R2 is -O- or -S-; each Z5 is independently C1 -C6 alkylene optionally substituted by one or more substituents independently selected from oxo, halo and hydroxy; and Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy) or an optionally substituted group selected from the group consisting of: C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted by one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl) and hydroxy; or a pharmaceutically acceptable salt thereof. 89. A compound according to claim 88, characterized in that the compound of Formula AA is a compound of Formula AA-1 R3 (R6'' )o HN O O (R7)p 1 B (R )m S A' N N H(R2)n. 90. A compound according to claim 88 or 89, characterized in that A' is a 6- to 10-membered heteroaryl. 91. A compound according to claim 88 or 89, characterized in that A' is a C6-C10 aryl. 92. A compound according to claim 88 or 89, characterized in that A' is a 5-membered heteroaryl comprising 2 or more heteroatoms and/or heteroatomic groups. 93. A compound according to claim 88 or 89, characterized in that A' is a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH and NR1. 94. A compound according to claim 88 or 89, containing characterized by the fact that A' is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, in which the heteroatom is not bonded to the position of the heteroaryl that is bonded to the chemical moiety S(O)(NHR3)= No. 95. Compound according to any one of claims 88 or 89 and 94, characterized in that A' is thiophenyl. 96. A compound according to any one of claims 88 or 89 and 92, characterized in that A' is thiazolyl. 97. A compound according to any one of claims 88 or 89 and 92, characterized in that A' is pyrazolyl. 98. Compound according to any one of claims 88 or 89 and 91, characterized in that A' is phenyl. 99. Compound according to any one of claims 88 to 98, characterized in that m=1 and n=0. 100. A compound according to any one of claims 88 or 89, 92, 96 and 99, characterized in that the optionally substituted ring A' is . 101. Compound according to any one of claims 88 or 89, 92, 96 and 99, characterized in that the ring R1 N optionally substituted A' is S. 102. A compound according to any one of claims 88 or 89, 92, 96 and 99, characterized in that the optionally substituted ring A' is . 103. Compound according to any one of claims 88 or 89, 92, 96 and 99, characterized in that the ring S R1 N optionally substituted A' is . 104. A compound according to any one of claims 88 or 89, 92, 97 and 99, characterized in that the optionally substituted ring A' is . 105. A compound according to any one of claims 88 or 89, 91, 98 and 99, characterized in that the optionally substituted ring A' is . 106. Compound according to any one of claims 88 to 98, characterized in that m=1 and n=1. 107. A compound according to any one of claims 88 to 89, 92, 96 and 106, characterized in that the optionally substituted ring A' is . 108. A compound according to any one of claims 88 or 89, 92, 97 and 106, characterized in that the optionally substituted ring A is . 109. A compound according to any one of claims 88 or 89, 92, 97 and 106, characterized in that the optionally substituted ring A is . 110. A compound according to any one of claims 88 or 89, 92, 96 and 106, characterized in that the optionally substituted ring A' is . 111. A compound according to any one of claims 88 or 89, 91, 98 and 106, characterized in that the optionally substituted ring A' is . 112. A compound according to any one of claims 88 to 111, characterized in that R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1- C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. 113. A compound according to any one of claims 88 to 112, characterized in that R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo or NR8R9. 114. A compound according to any one of claims 88 to 112, characterized in that R 1 , when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluorine; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 115. A compound according to any one of claims 88 to 114, characterized in that R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluorine. 116. A compound according to any one of claims 88 to 115, characterized in that R 1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. 117. A compound according to any one of claims 88 to 115, characterized in that R1 is fluorine. 118. A compound according to any one of claims 88 to 98 and 106 to 117, characterized in that R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by a or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; heterocy- 3- to 7-membered chloroalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. 119. A compound according to any one of claims 88 to 98 and 106 to 118, characterized in that R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted by a or more hydroxyl, halo or NR8R9. 120. A compound according to any one of claims 88 to 98 and 106 to 118, characterized in that R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl ; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluorine; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 121. A compound according to any one of claims 88 to 98 and 106 to 120, characterized in that R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluorine. 122. A compound according to any one of claims 88 to 98, 106, 108 and 110, characterized in that R1 and R2 are on adjacent atoms and, considered together with the atoms connecting them, independently form a C4-C12 monocyclic or bicyclic carbocyclic ring (e.g. C5 or C6 carbocyclic ring) or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then, the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O ) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g. methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g. isopropoxy), OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl) and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5- to 10-membered heteroaryl, the C3-C10 cycl 3- to 10-membered alkyl and heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo (e.g., fluorine), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g. amino, methylamino or dimethylamino no), =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 123. A compound according to any one of claims 88 to 98, 106, 108 and 110, characterized in that R1 and R2 are on adjacent atoms and, taken together with atoms connecting them, independently form a ring C5-C6 monocyclic or bicyclic carbocyclic optionally substituted independently by one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxy, azetidinyl, oxetanyl, wherein methyl, isopropoxy, a azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluorine, amino, methylamino and dimethylamino; or R1 and R2 are on adjacent atoms and, taken together, independently form: , , or , each optionally substituted by one or more substituents independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, in that methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluorine, amino, methylamino and dimethylamino; wherein the asterisk represents a point of attachment to a carbon atom; and o represents a point of attachment to a carbon or a nitrogen atom. 124. A compound according to any one of claims 88 to 98, 106, 108 and 110, characterized in that R1 and R2 are on adjacent atoms and, considered together with the atoms connecting them, independently form at least one C4-C12 bicyclic spirocyclic carbocyclic ring, wherein the carbocyclic ring is optionally substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents, each independently selected from hydroxy, fluorine, amino, methylamino and dimethylamino. 125. A compound according to any one of claims 88 to 98, 106, 108 and 110, characterized in that R1 and R2 are on adjacent atoms and, considered together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from among O, NH, NR13 , S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S , S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein methyl, isopropoxy, azetidinyl and oxetanyl are optionally substituted by one or more substituents each independently selected from hydroxy, fluorine, amino, methylamino and dimethylamino. 126. A compound according to any one of claims 88 or 89, 92 and 96, characterized in that A' is thiazolyl (eg 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted by hydroxy (e.g. 2-hydroxy-2- propyl); and R2, when present, is C1-C6 alkyl optionally substituted with hydroxy (e.g., methyl, hydroxymethyl or hydroxyethyl). 127. A compound according to any one of claims 88 or 89, 92 and 97, characterized in that A' is pyrazolyl (eg, 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted by 1 to 3 halo (e.g. fluorine). 128. A compound according to any one of claims 88 or 89, 91 and 98, characterized in that A' is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted by NR8R9 (e.g. dimethylamino); and R2, when present, is halo (e.g., fluorine). 129. A compound according to any one of claims 88 or 89 and 94 or 95, characterized in that A' is thiophenyl; m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. isopropyl, 2-hydroxy-2-propyl or 1-propanoyl). 130. A compound according to any one of claims 88 or 89, characterized in that the optionally substituted ring A' is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is attached to the chemical moiety S(O)(NHR3)=N; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring cyclic includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by an o u more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1 -C6 alkyl, C6-C10 aryl and CONR8R9. 131. A compound according to any one of claims 88 or 89, 92, 97 and 130, characterized in that the optionally substituted ring A' is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O) two; and b) when one or both adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2 )C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by an o u more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1 -C6 alkyl, C6-C10 aryl and CONR8R9. 132. A compound according to any one of claims 88 or 89, 92 and 130, characterized in that the optionally substituted ring A' is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring, wherein a) when each of the adjacent atoms is a carbon atom, so the heterocyclic ring includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2; and b) when one or both of the adjacent atoms is a nitrogen atom (or atoms), then the heterocyclic ring includes from 0 to 2 heterocyclic rings. roatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2 (in addition to the aforementioned nitrogen atom (or atoms) bonded to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and CONR8R9, wherein C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3-membered heterocycloalkyl to 10 members are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 133. A compound according to any one of claims 88 or 89 and 94 to 95, characterized in that the optionally substituted ring A' is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms and, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring that includes from 1 to 3 heterocyclic rings. heteroatomic atoms and/or groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted by one or more substituents, each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, S( O2)C6-C10 aryl, C6-C10 aryl, 5-10 membered heteroaryl, C3- C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, the C1-C6 alkoxy, the S(O2)C6-C10 aryl, the C6-C10 aryl, the 5-10-membered heteroaryl, the C3-C10 cycloalkyl and the 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 134. A compound according to any one of claims 88 or 89, 92 and 97, characterized in that the optionally substituted ring A is , wherein Rx is selected from the group consisting of H and C1- C6 alkyl (e.g. methyl); Z1 is selected from the group consisting of O, NH and -CH2- optionally substituted by 1 to 2 R20; Z2 is selected from the group consisting of NH and -CH2- optionally substituted by 1-2 R20; Z3 is selected from the group consisting of -CH2- optionally substituted by 1 to 2 R20, -CH2CH2- optionally substituted by 1-2 R20, and -CH2CH2CH2- optionally substituted by 1-2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g. fluorine), oxo, C1-C6 alkyl (e.g. methyl or ethyl) optionally substituted by an R21, C1-C6 alkoxy (e.g. methoxy , ethoxy or isopropoxy) optionally substituted by an R21, NR8R9, 3 to 10 membered heterocycloalkyl (e.g. azetidinyl or pyrrolidinyl) optionally substituted by an R21 or a pair of R20 on the same atom taken together with the connecting atom the same independently form a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted by OS(O)2Ph; R21 is selected from the group consisting of halo (eg fluorine), NR8R9, C2-C6 alkynyl (eg ethynyl) and C1-C6 alkoxy (eg methoxy); R8 and R9 at each occurrence are independently selected from hydrogen, C1-C6 alkyl (eg methyl or ethyl), COR13 and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (eg methyl or t-butyl) and C1-C6 haloalkyl (eg trifluoromethyl). 135. A compound according to any one of claims 88 or 89 and 97, characterized in that the optionally substituted ring A is , wherein Z4 is selected from the group consisting of -CH2-, -C (O)- and NH; Z5 is selected from the group consisting of O, NH, N-CH3 and -CH2-. 136. A compound according to any one of claims 88 to 135, characterized in that B is pyridyl or an N-oxide thereof. 137. A compound according to any one of claims 88 to 136, characterized in that B is 3-pyridyl or an N-oxide thereof. 138. Compound according to any one of claims 88 to 137, characterized in that o=2 and p=1. 139. A compound according to any one of claims 88 to 138, characterized in that the substituted ring B is N R 6'' R7 R 6'' . 140. A compound according to any one of claims 88 to 139, characterized in that each R6'' is independently selected from the group consisting of: C1-C6 alky- la, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1 -C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO (4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 141. A compound according to any one of claims 88 to 140, characterized in that each R6'' is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl and C6-C10 aryl. 142. A compound according to any one of claims 88 to 141, characterized in that each R6'' is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 143. A compound according to any one of claims 88 to 142, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO(heterocycloalkyl with 4 to 6 members) and NHCOC2-C6 alkynyl. 144. A compound according to any one of claims 88 to 143, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6-C10 aryl. 145. A compound according to any one of claims 88 to 144, characterized in that each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 146. A compound according to any one of claims 88 to 136, characterized in that B is 4-pyridyl or an N-oxide thereof. 147. Compound according to any one of claims 88 to 136 and 146, characterized in that o=2 and p=0. 148. Compound according to any one of claims 88 to 136 and 146 or 147, characterized in that the ring R6'' N substituted B is R6''. 149. A compound according to any one of claims 88 to 136 and 146 to 148, characterized in that each R6'' is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1- C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5 to 5-membered heteroaryl 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) members), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 150. A compound according to any one of claims 88 to 136 and 146 to 149, characterized in that each R6'' is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl. 151. A compound according to any one of claims 88 to 136 and 146 to 150, characterized in that each R6'' is isopropyl. 152. Compound according to any one of claims 88 to 136 and 146, characterized in that o=2 and p=2. 153. A compound according to any one of claims 88 to 136, 146 and 152, characterized in that the ring R7 R6'' N substituted R7 B is R6''. 154. A compound according to any one of claims 88 to 136, 146 and 152 or 153, characterized in that each R6'' is independently selected from the group consisting of: C1-C6 alkyl, C3 -C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected. from among hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 155. A compound according to any one of claims 88 to 136, 146 and 152 to 154, characterized in that each R6'' is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6-C10 aryl. 156. A compound according to any one of claims 88 to 136, 146 and 152 to 155, characterized in that each R6'' is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 157. A compound according to any one of claims 88 to 136, 146 and 152 to 156, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected. from among hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 158. A compound according to any one of claims 88 to 136, 146 and 152 to 157, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6 -C10 aryl. 159. A compound according to any one of claims 88 to 136, 146 and 152 to 158, characterized in that each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 160. A compound according to any one of claims 88 or 89, 139 to 142 and 153 to 159, characterized in that a pair of R6'' and R7 on adjacent atoms, considered together with the atoms that connecting them independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9 , =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 161. A compound according to any one of claims 88 or 89, 139 to 142 and 153 to 159, characterized in that a pair of R6'' and R7 on adjacent atoms, considered together with the atoms that connecting them independently form at least one C4-C8 carbocyclic ring, where the carbon- cyclic is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 162. Compound according to claim 160 or 161, characterized in that the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted by one or more oxo, CH3 or hydroxy. 163. Compound according to claim 162, characterized by the fact that the C5 carbocyclic ring is replaced by a CH3. 164. Compound according to claim 162, characterized by the fact that the C5 carbocyclic ring is geminally replaced by two CH3. 165. A compound according to claim 160 or 161, characterized in that the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a ring with 5 members and a ring with 3 members. 166. A compound according to any one of claims 88 or 89 and 96, wherein the optionally substituted ring A' is thiazolyl (eg 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1 (e.g. n is 1); R1 is C1-C6 alkyl optionally substituted by hydroxy (e.g. 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted by hydroxyl (e.g. methyl, hydroxymethyl or hydroxyethyl). 167. A compound according to any one of claims 88 to 89 and 97, wherein the optionally substituted ring A' is pyrazolyl (eg, 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted by 1 to 3 halo (e.g. fluorine (e.g. R1 is C1-C6 alkyl substituted by 2 to 3 fluorine)). 168. A compound according to any one of claims 88 or 89 and 98, characterized in that the optionally substituted ring A' is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted by NR8R9 (e.g. dimethylamino); and R2, when present, is halo (e.g., fluorine (e.g., R1 is C1-C6 alkyl substituted by 2 to 3 fluorine)). 169. Compound according to any one of claims 88 or 89, 126 to 135 and 166 to 168, characterized in that (Y)q N that the substituted ring B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring. 170. Compound according to any one of claims 88 or 89, 126 to 135 and 166 to 168, characterized in that (Y)q N(R7)p which substituted ring B is; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring. 171. Compound according to any one of claims 88 or 89, 126 to 135 and 166 to 168, characterized in that R6'' N R6''(R7)p which substituted ring B is; each R6'' is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (e.g. fluorine); p is 0 or 1. 172. Compound according to any one of claims 88 or 89, 126 to 135 and 166 to 168, characterized in that R6'' N R6''(R7)p which substituted ring B is; each R6'' is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (e.g. fluorine); p is 0 or 1. 173. Compound according to claim 88, characterized in that the compound of Formula AA is a compound of R3 (R 6)o HN O O (R 7)p 1 B (R )m' S A'' N N H Formula AA-2(R2) n'. 174. Composite, in accordance with any of the claims cations 88 and 173, characterized by the fact that A'' is thiophenyl. 175. Compound according to any one of claims 88 and 173 to 174, characterized in that m'=1 and n'=0. 176. A compound according to any one of claims 88 and 173 to 175, characterized in that the optionally substituted ring A'' is . 177. A compound according to any one of claims 88 and 173 to 175, characterized in that the optionally substituted ring A'' is . 178. A compound according to any one of claims 88 and 173 to 177, characterized in that R1, when present, is independently selected from the group consisting of a C1-C6 alkyl optionally substituted by one or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. 179. A compound according to any one of claims 88 and 173 to 178, characterized in that R1, when present, is independently selected from the group consisting of a C1-C6 alkyl optionally substituted by one or more hydroxyl, halo or NR8R9. 180. A compound according to any one of claims 88 and 173 to 178, characterized in that R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl ; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluorine; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 181. A compound according to any one of claims 88 and 173 to 180, characterized in that R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluorine. 182. A compound according to any one of claims 88 and 173 to 181, characterized in that R1, when present, is 2-hydroxy-2-propyl or 1,2-dihydroxy-2- propyl. 183. A compound according to any one of claims 88 and 173 to 181, characterized in that R1 is fluorine. 184. A compound according to any one of claims 88, 173, 174 and 178 to 183, characterized in that R2, when present, is independently selected from the group consisting of a C1-C6 alkyl optionally substituted by a or more hydroxy, C1-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. 185. A compound according to any one of claims 88, 173, 174 and 178 to 184, characterized in that R2, when present, is independently selected from the group consisting of a C1-C6 alkyl optionally substituted by a or more hydroxyl, halo or NR8R9. 186. A compound according to any one of claims 88, 173, 174 and 178 to 184, characterized in that R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2 -ila; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluorine; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 187. A compound according to any one of claims 88, 173, 174 and 178 to 186, characterized in that R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluorine. 188. A compound according to any one of claims 88 and 173 to 187, characterized in that B is pyridyl or an N-oxide thereof. 189. A compound according to any one of claims 88 and 173 to 188, characterized in that B is 3-pyridyl or an N-oxide thereof. 190. Compound according to any one of claims 88 and 173 to 189, characterized in that o=2 and p=1. 191. A compound according to any one of claims 88 and 173 to 190, characterized in that the substituted ring N R6 R7 ido B is R6 . 192. A compound according to any one of claims 88 and 173 to 191, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5 to 5-membered heteroaryl 10 members, OCOC1-C6 alkyl, OCOC6- C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl members) and NHCOC2-C6 alkynyl. 193. A compound according to any one of claims 88 and 173 to 192, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl and C6-C10 aryl. 194. A compound according to any one of claims 88 and 173 to 193, characterized in that each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 195. A compound according to any one of claims 88, 173 to 189 and 192 to 194, characterized in that each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl , C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each one independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5-10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) to 10-membered), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 196. Compound according to any one of claims 88, 173 to 189 and 192 to 195, characterized in that each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl. 197. A compound according to any one of claims 88, 173 to 189 and 192 to 196, characterized in that each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 198. A compound according to any one of claims 88 and 173 to 188, characterized in that B is 4-pyridyl or an N-oxide thereof. 199. Compound according to claim 88, 173 to 188 and 198, characterized in that o=2 and p=0. 200. Compound according to any one of claims 88, 173 to 188 and 198 or 199, characterized in that R6 N substituted ring B is R6 . 201. A compound according to any one of claims 88, 173 to 188 and 198 to 200, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected. from among hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 202. A compound according to any one of claims 88, 173 to 188 and 198 to 201, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl. 203. A compound according to any one of claims 88, 173 to 188 and 198 to 202, characterized in that each R6 is isopropyl. 204. Compound according to any one of claims 88, 173 to 188 and 198, characterized in that o=2 and p=2. 205. Compound according to any one of claims 88, 173 to 188, 198 and 204, characterized in that the ring R7 R6 N substituted R7 B is R6. 206. A compound according to any one of claims 88, 173 to 188, 198 and 204 to 205, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3 -C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5 to 10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted with one or more substituents, each one independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5 to 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 207. A compound according to any one of claims 88, 173 to 188, 198 and 204 to 206, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3 -C7 cycloalkyl, halo and C6-C10 aryl. 208. A compound according to any one of claims 88, 173 to 188, 198 and 204 to 207, characterized in that each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 209. A compound according to any one of claims 88, 173 to 188, 198 and 204 to 208, characterized in that each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl , C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently - carefully selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5 to 10 members, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(heteroaryl 5 to 10 membered), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 210. A compound according to any one of claims 88, 173 to 188, 198 and 204 to 209, characterized in that each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl , C3-C7 cycloalkyl, halo and C6-C10 aryl. 211. A compound according to any one of claims 88, 173 to 188, 198 and 204 to 210, characterized in that each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 212. A compound according to any one of claims 88, 173 to 188, 198 and 204-210, characterized in that a pair of R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S (O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, = NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 213. A compound according to any one of claims 88, 173 to 188, 198 and 204 to 210, characterized in that a pair of R6 and R7 on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkyl, C6-C10 aryl and CONR8R9. 214. Compound according to claim 212 or 213, characterized in that the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted by one or more oxo, CH3 or hydroxy. 215. Compound according to claim 214, characterized by the fact that the C5 carbocyclic ring is replaced by a CH3. 216. Compound, according to claim 214, characterized by the fact that the C5 carbocyclic ring is geminally substituted by two CH3. 217. A compound according to claim 212 or 213, characterized in that the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a ring with 5 members and a ring with 3 members. 218. A compound according to claim 173, characterized in that A'' is thiophenyl (eg 2-thiophenyl); m' is 1; n' is 0; and R1 is C1-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. isopropyl, 2-hydroxy-2-propyl or 1-propanoyl). 219. A compound according to any one of claims 173 and 218, characterized in that A'' is 2-thiophenyl. 220. A compound according to any one of claims 173 and 218, characterized in that the substituted ring B(Y)q N is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein, when two Y's are bonded to the same carbon, the two Y's are taken together with the carbon to which they are bonded to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring. 221. A compound according to any one of claims 173 and 218, characterized in that the substituted ring B(Y)q N(R7)p is ; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring. 222. A compound according to any one of claims 173 and 218, characterized in that the substituted ring B R6 N R6(R7)p is ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluorine); p is 0 or 1. 223. A compound according to any one of claims 173 and 218, characterized in that the substituted ring B R6 N 7 is R 6 (R )p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluorine); p is 0 or 1. 224. A compound according to claim 88, characterized in that the compound of Formula AA is a compound of R3 (R6) o HN O O (R7)p 1' B (R )m'' S A'' N N H Formula AA-3(R2')n''. 225. A compound according to any one of claims 88 and 224, characterized in that A'' is thiophenyl. 226. Compound according to any one of claims 88 and 224 or 225, characterized in that m''=1 and n''=1. 227. A compound according to any one of claims 88 and 224 to 226, characterized in that the optional ring R1' Finally substituted A'' is R2'. 228. A compound according to any one of claims 88 and 224 to 226, characterized in that the optional ring R2' S 1' finally substituted A'' is R . 229. A compound according to any one of claims 88 and 224 to 226, characterized in that the optionally substituted ring A'' is . 230. A compound according to any one of claims 88 and 224 to 229, characterized in that R1', when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted by one or plus hydroxy, C2-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; Cl; BR; I; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. 231. A compound according to any one of claims 88 and 224 to 230, characterized in that R1', when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted by one or plus hydroxyl or NR8R9. 232. A compound according to any one of claims 88 and 224 to 230, characterized in that R1', when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; isopropyl; ethyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 233. A compound according to any one of claims 88 and 224 to 232, characterized in that R 1' is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. 234. A compound according to any one of claims 88 and 224 to 233, characterized in that R2', when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted by one or plus hydroxy, C2-C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; Cl; BR; I; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. 235. A compound according to any one of claims 88 and 224 to 234, characterized in that R2, when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted by one or more hydroxyl, halo or NR8R9. 236. A compound according to any one of claims 88 and 224 to 234, characterized in that R 2 ', when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; isopropyl; ethyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1- cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 237. A compound according to any one of claims 88 and 224 to 236, wherein R 2' is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. 238. A compound according to any one of claims 88, 224 to 226 and 228 or 229, characterized in that a pair of R1' and R2' on adjacent atoms, considered together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6 -C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, where C1-C6 alkyl, C 1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, CO-OC1- C6 alkyl, C6-C10 aryl and CONR8R9. 239. A compound according to any one of claims 88 and 224 to 238, characterized in that B is pyridyl or an N-oxide thereof. 240. A compound according to any one of claims 88 and 224 to 239, characterized in that B is 3-pyridyl or an N-oxide thereof. 241. Compound according to any one of claims 88 and 224 to 240, characterized in that o=2 and p=1. 242. A compound according to any one of claims 88 and 224 to 241, characterized in that the substituted ring N R6 R7 ido B is R6 . 243. Compound according to claims 88 and 224 to 242, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1 -C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1 -C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO (4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 244. A compound according to any one of claims 88 and 224 to 243, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl and C6-C10 aryl. 245. A compound according to any one of claims 88 and 224 to 244, characterized in that each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 246. A compound according to any one of claims 88 and 224 to 245, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5 to 5-membered heteroaryl 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) members), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 247. A compound according to any one of claims 88 and 224 to 246, characterized in that each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6-C10 aryl. 248. A compound according to any one of claims 88 and 224 to 247, characterized in that each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 249. Composite, in accordance with any of the claims 88 and 224 to 239, characterized in that B is 4-pyridyl or an N-oxide thereof. 250. Compound according to any one of claims 88, 224 to 239 and 249, characterized in that o=2 and p=0. 251. Compound according to any one of claims 88, 224 to 239 and 249 or 250, characterized in that R6 N substituted ring B is R6 . 252. A compound according to any one of claims 88, 224 to 239 and 249 to 251, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected. from among hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 253. A compound according to any one of claims 88, 224 to 239 and 249 to 252, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl. 254. Composite, in accordance with any of the claims 88, 224 to 239 and 249 to 253, characterized in that each R6 is isopropyl. 255. Compound according to any one of claims 88, 224 to 239 and 249 to 254, characterized in that o=2 and p=2. 256. Compound according to any one of claims 88, 224 to 239 and 249 to 255, characterized in that R7 R6 N R7 substituted ring B is R6 . 257. A compound according to any one of claims 88, 224 to 239 and 249 to 256, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected. from among hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl , OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl) , NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 258. A compound according to any one of claims 88, 224 to 239 and 249 to 257, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6 -C10 aryl. 259. A compound according to any one of claims 88, 224 to 239 and 249 to 258, characterized in that each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 260. A compound according to any one of claims 88, 224 to 239 and 249 to 259, characterized in that each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl , C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each one independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, heteroaryl with 5-10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-membered heteroaryl) to 10-membered), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 261. A compound according to any one of claims 88, 224 to 239 and 249 to 260, characterized in that each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl , C3-C7 cycloalkyl, halo and C6-C10 aryl. 262. A compound according to any one of claims 88, 224 to 239 and 249 to 261, characterized in that each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 263. Composite, in accordance with any of the claims cations 88, 224 to 239 and 249 to 262, characterized by the fact that a pair of R6 and R7 on adjacent atoms, considered together with the atoms that connect them, independently form at least one C4-C8 carbocyclic ring or at least one least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or ring heterocyclyl is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, CO-OC1-C6 alkyl, C6 -C10 aryl and CONR8R9. 264. A compound according to any one of claims 88, 224 to 239 and 249 to 262, characterized in that a pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, CO-OC1-C6 alkyl, C6-C10 aryl and CONR8R9. 265. A compound according to any one of claims 263 to 264, wherein the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted by one or more oxo, CH3 or hydroxy. 266. Compound according to claim 265, characterized by the fact that the C5 carbocyclic ring is replaced by a CH3. 267. Compound according to claim 265, characterized by the fact that the C5 carbocyclic ring is geminally replaced by two CH3. 268. A compound according to claim 263 or 264, characterized in that the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a ring with 5 members and a ring with 3 members. 269. A compound according to any one of claims 88 and 224, characterized in that A'' is thiophenyl (eg, 2-thiophenyl); m'' is 1; n'' is 1; R1' is C2-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. 2-hydroxy-2-propyl); and R2' is C2 -C6 alkyl optionally substituted by hydroxyl or oxo (e.g. 2-hydroxy-2-propyl). 270. A compound according to any one of claims 88, 224 and 269, characterized in that the ring replaces - (Y)q N of B is (Z)r; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are bonded to the same carbon, the two Z's are taken together with the carbon to which they are bonded to form a cyclopropyl ring. 271. A compound according to any one of claims 88, 224 and 269, characterized in that the replaceable ring (Y)q N(R7)p of B is ; R7 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are bonded to the same carbon, the two Y's are taken together with the carbon to which they are bonded to form a cyclopropyl ring. 272. A compound according to any one of claims 88, 224 and 269, characterized in that the ring replaces R6 N R6(R7)p of B is ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluorine); p is 0 or 1. 273. A compound according to any one of claims 88, 224 and 269, characterized in that the ring replaces R6 N 7 of B is R 6 (R )p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluorine); and p is 0 or 1. 274. A compound according to claim 88, characterized in that the compound of Formula AA is a compound of R3 (R6) o HN O O (R7)p 1 B' (R )m''' S A'' N N H Formula AA-4(R2'')n'''. 275. A compound according to any one of claims 88 and 274, characterized in that A'' is thiophenyl. 276. A compound according to any one of claims 88 and 274 or 275, characterized in that the optional ring R1 Finally substituted A'' is R2''. 277. A compound according to any one of claims 88 and 274 or 275, characterized in that the optional ring R2'' S 1 finally substituted A'' is R . 278. A compound according to any one of claims 88 and 274 or 275, characterized in that the optionally substituted ring A'' is . 279. A compound according to any one of claims 88 and 274 to 278, characterized in that R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1- C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered op-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. 280. A compound according to any one of claims 88 and 274 to 279, characterized in that R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo or NR8R9. 281. A compound according to any one of claims 88 and 274 to 279, characterized in that R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluorine; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 282. A compound according to any one of claims 88 and 274 to 281, characterized in that R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluorine. 283. Composite, in accordance with any of the claims 88 and 274 to 282, characterized in that R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. 284. A compound according to any one of claims 88 and 274 to 282, characterized in that R1 is fluorine. 285. A compound according to any one of claims 88 and 274 to 284, characterized in that R2'' is fluorine. 286. A compound according to any one of claims 88 and 274 to 284, characterized in that R2'' is methyl. 287. A compound according to any one of claims 88, 274 or 275 and 277 or 278, characterized in that a pair of R1 and R2'' on adjacent atoms, taken together with the atoms connecting them, independently form a monocyclic or bicyclic C4-C12 carbocyclic ring or a monocyclic or bicyclic 5- to 12-membered heterocyclic ring that includes from 1 to 3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, =NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1 -C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted by one or more substituents, each one independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, =NR10, COOC1-C6 alkyl, C6 -C10 aryl and CONR8R9. 288. Composite, in accordance with any of the claims 88 and 274 to 287, characterized by the fact that o=2 and p=1. 289. A compound according to any one of claims 88 and 274 to 288, characterized in that the substituted ring N R6 R7 ido B is R6 . 290. A compound according to any one of claims 88 and 274 to 289, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5 to 5-membered heteroaryl 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) members), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 291. A compound according to any one of claims 88 and 274 to 290, characterized in that each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl and C6-C10 aryl. 292. A compound according to any one of claims 88 and 274 to 291, characterized in that each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 293. A compound according to any one of claims 88 and 274 to 292, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5-10 membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, the C1-C6 haloalkyl, the C3-C7 cycloalkyl, and the 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, =NR10, CO-OC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5 to 5-membered heteroaryl 10 membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) members), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 294. A compound according to any one of claims 88 and 274 to 293, characterized in that each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo and C6-C10 aryl. 295. A compound according to any one of claims 88 and 274 to 294, characterized in that each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluorine and phenyl. 296. A compound according to any one of claims 88 and 274 to 278, wherein the optionally substituted ring A'' is thiophenyl (eg, 2-thiophenyl); R1 is C1-C6 alkyl optionally substituted by hydroxyl or oxo (e.g. methyl or 2-hydroxy-2-propyl); and R2'' is methyl. 297. Composite, in accordance with any of the claims cations 88, 274 to 278 and 296, characterized by the fact that the ring R6 N 7 substituted B is R 6 (R )p ; each R6 is independently selected from C1-C6 alkyl (e.g. isopropyl); each R7 is independently selected from halo (eg, fluorine); p is 0 or 1. 298. A compound according to any one of claims 1 to 297, characterized in that R3 is hydrogen. 299. A compound according to any one of claims 1 to 297, characterized in that R3 is CHO. 300. Compound according to claim 88, characterized in that the compound of Formula AA is a compound of (R 6') o H 2N OO (R7') p 1 B'' (R ) m' '' SS N N H Formula AA-5 (R 2'') n'''. 301. Compound according to any one of claims (R 1) m''' S cations 88 and 300, characterized in that (R 2'') n''' is R1 S R2''. 302. Compound according to any one of claims 88 and 300, characterized in that (R 2'') n''' is R2'' S R1 . 303. A compound according to any one of claims 88 and 300 to 302, characterized in that R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxy, C1- C6 alkyl optionally substituted by one or more halo, oxo, C1-C6 alkoxy or NR8R9; C3-C7 cycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by an a three hydroxy, halo, NR8R9 or oxo; 3- to 7-membered heterocycloalkyl optionally substituted by one or more hydroxy, halo, oxo, C1-C6 alkyl or NR8R9, wherein the C1-C6 alkoxy or the C1-C6 alkyl is further optionally substituted by one to three hydroxy, halo, NR8R9 or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(heteroaryl with 5 to 10 members); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO (heteroaryl with 5 to 10 members); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; heteroaryl with 5 to 10 members; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. 304. A compound according to any one of claims 88 and 300 to 302, characterized in that R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted by one or more hydroxyl, halo or NR8R9. 305. A compound according to any one of claims 88 and 300 to 302, characterized in that R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluorine; chlorine; phenyl; pyridyl; pyrazolyl; S(O2)CH3 and S(O2)NR11R12. 306. A compound according to any one of claims 88 and 300 to 305, characterized in that R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluorine. 307. A compound according to any one of claims 88 and 300 to 305, wherein R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. 308. A compound according to any one of claims 88 and 300 to 305, characterized in that R1 is fluorine. 309. A compound according to any one of claims 88 and 300 to 308, characterized in that R2'' is F. 310. A compound according to any one of claims 88 and 300 to 308, characterized in that R2'' is methyl. 311. Compound according to any one of claims 88 and 300 to 310, characterized in that o=2 and p=0. 312. A compound according to any one of claims 88 and 300 to 311, characterized in that the substituent ring R 6' Nido B is R 6' . 313. A compound according to any one of claims 88 and 300 to 312, characterized in that each R6' is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3-C7 cycloalkyl , C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the unbranched C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each one independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4 to 6 membered heterocycloalkyl, C6-C10 aryl, 5 to 10 membered heteroaryl membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl) ), NHCO(4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 314. A compound according to any one of claims 88 and 300 to 313, characterized in that each R6' is independently selected from the group consisting of: C1-C6 unbranched alkyl and C3-C7 cycloalkyl . 315. Compound according to any one of claims 88 and 300 to 310, characterized in that o=2 and p=2. 316. A compound according to any one of claims 88, 300 to 310 and 315, characterized in that the ring R7' R6' N substituted R7' B is R6'. 317. A compound according to any one of claims 88, 300 to 310 and 315 or 316, characterized in that each R6' is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the unbranched C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents, each one independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1- C6 alkyl, OCOC6-C10 aryl, OCO(5-10 membered heteroaryl), OCO(4-6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5-10 membered heteroaryl), NHCO( 4- to 6-membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 318. A compound according to any one of claims 88, 300 to 310 and 315 to 317, characterized in that each R6' is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3- C7 cycloalkyl, halo and C6-C10 aryl. 319. A compound according to any one of claims 88, 300 to 310 and 315 to 317, characterized in that each R6' is independently selected from the group consisting of: methyl, cyclopropyl, fluorine and phenyl. 320. A compound according to any one of claims 88, 300 to 310 and 315 to 319, characterized in that each R7', when present, is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR8R9 and 4- to 6-membered heterocycloalkyl, wherein the unbranched C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 4- to 6-membered heterocycloalkyl are optionally substituted by one or more substituents , each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, =NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl membered, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5 to 10 membered heteroaryl), OCO(4 to 6 membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5 to 10 membered heteroaryl), NHCO(4 to 6 membered heterocycloalkyl) and NHCOC2-C6 alkynyl. 321. A compound according to any one of claims 88, 300 to 310 and 315 to 320, characterized in that each R7', when present, is independently selected from the group consisting of: C1-C6 unbranched alkyl, C3-C7 cycloalkyl, halo and C6-C10 aryl. 322. A compound according to any one of claims 88, 300 to 310 and 315 to 321, characterized in that each R7', when present, is independently selected from the group consisting of: methyl, cyclopropyl , fluorine and phenyl. 323. A compound according to any one of claims 88, 300 to 310 and 315 to 322, characterized in that a pair of R6' and R7' on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O) and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally substituted independently by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9 , CH2NR8R9, =NR10, CO-OC1-C6 alkyl, C6-C10 aryl and CONR8R9. 324. A compound according to any one of claims 88, 300 to 310 and 315 to 322, characterized in that a pair of R6' and R7' on adjacent atoms, considered together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted by one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, =NR10, CO-OC1-C6 alkyl, C6-C10 aryl and CONR8R9. 325. Compound according to claim 323 or 324, characterized in that the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted by one or more oxo, CH3 or hydroxy. 326. Compound according to claim 325, characterized by the fact that the C5 carbocyclic ring is replaced by a CH3. 327. Compound according to claim 325, characterized by the fact that the C5 carbocyclic ring is geminally substituted by two CH3. 328. A compound according to claim 323 or 324, characterized in that the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a ring with 5 members and a ring with 3 members. 329. The compound of claim 300, chac-(Y)q N terized by the fact that the substituted ring B'' is (Z)r ; q is 0, 1 or 2; r is 0, 1 or 2; wherein each of Y and Z is independently selected from C1 -C6 alkyl (e.g. methyl) and hydroxy; or wherein, when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring; or wherein, when two Z's are attached to the same carbon, the two Z's are taken together with the carbon to which they are attached to form a cyclopropyl ring. 330. A compound according to claim 300, characterized by (Y)q N (R7' )p terized by the fact that the substituted ring B'' is ; R7' is selected from C1-C6 unbranched alkyl (eg methyl or ethyl), C6-C10 aryl (eg phenyl) and C3-C10 cycloalkyl (eg cyclopropyl); p is 0, 1 or 2; q is 0, 1 or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g. methyl) and hydroxy; or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring. 331. Compound, characterized in that it is selected from the group consisting of the compounds below: Compound Structure post Structure nº 101 141aa 101a 141ab 101b 141b Composite Structure post Structure no. 102 141ba 102a 141bb 102b 145 103 145a Composite Structure post Structure no. 103aa 145b 103ab 147 103ba 147b 103bb 148 Composite Structure post Structure no. 104 148a 104a 148b 104b 149 105 149a Composite Structure post Structure no. 105 to 150 105b 150a 106 150b 106 to 151 Composite Structure post Structure no. 106b 152 107 153 107a 153a 107b 153b Composite Structure post Structure no. 110 154 114 154a 114a 154b 114b 155 Composite Structure post Structure no. 115 155a 116 155b 116a 156b 116b 157b Composite Structure post Structure no. 117 158 117a 158a 117b 159 118 159a Composite Structure post Structure no. 118a 159b 118b 160 119 160a 119 to 161 Composite Structure post Structure no. 119b 161a 120 161b 121 162 121a 162aa 121b 162ab Composite Structure post Structure no. 122 162ba 122a 162bb (R,R) 122b 163 123 163a Composite Structure post Structure no. 124 163b 124 to 164 124b 164a 125 165 Composite Structure post Structure nº 125a 165a 125b 165b 126 166 the NH2 S S O N 126a 167 HO N HN N 126b 167a Composite Structure post Structure nº 127 167b 127a 168 NH2 O THE s N NH 127b S 168a HO N 128 168aa Composite Structure post Structure no. 128a 168ab 128b 168b 129 168ba 129a to 168bb 129ba 169a 129bb 169b Composite Structure post Structure no. 130 170 130b 171 131 172 131a 172a 131aa 172bb Composite Structure post Structure no. 131b 173 131c 173a 131d 173b 131 and 174 131f 174a 131g 174b 132b 175 Composite Structure post Structure no. 133 175a 134 175b 134a to 176 134ab 177 134b 178 Composite Structure post Structure no. 134bb 179 135 180 136 180a 136a 180b 136b 181 137 to 182 Composite Structure post Structure no. 138 183 139 183a 140 183b 140a 183c Composite Structure post Structure no. 140a to 183d 140ab 184a 140b 184b 140b 184c 141 184d Compound Structure post Structure nº 141a 201 201a and pharmaceutically acceptable salts thereof. 332. Compound, characterized in that it is selected from the group consisting of the compounds in Table 1C and pharmaceutically acceptable salts thereof. 333. Compound, characterized in that it is selected from the group consisting of the compounds in Table 1D and pharmaceutically acceptable salts thereof. 334. A compound, characterized in that it is selected from the group consisting of the compounds in Table 1E or Table 1F (eg Table 1E; eg Table 1F) and pharmaceutically acceptable salts thereof. 335. A compound according to any one of claims 1 to 330, characterized in that sulfur in the chemical moiety S(=O)(NHR3)=N- has (S) stereochemistry. 336. A compound according to any one of claims 1 to 330, characterized in that sulfur in the chemical moiety S(=O)(NHR3)=N- has (R) stereochemistry. 337. Pharmaceutical composition, characterized in that it comprises a compound or salt, as defined in any one of claims 1 to 336, and one or more pharmaceutically acceptable excipients. 338. Method to modulate NLRP3 activity, characterizing The method comprises contacting NLRP3 with an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 339. Method according to claim 338, characterized by the fact that the modulation comprises antagonizing NLRP3. 340. Method according to claim 338 or 339, characterized in that it is performed in vitro. 341. Method according to claim 338 to 340, characterized in that the method comprises placing a sample comprising one or more cells comprising NLRP3 in contact with the compound. 342. Method according to any one of claims 338 to 339 and 341, characterized in that it is carried out in vivo. 343. The method of claim 342, wherein the method comprises administering the compound to an individual who has a disease in which NLRP3 signaling contributes to the pathology and/or the symptoms and/or the disease progression. 344. Method, according to claim 343, characterized by the fact that the individual is a human being. 345. A method of treating a disease, disorder or condition which is a metabolic disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 346. Method according to claim 345, characterized in that the metabolic disorder is Type 2 diabetes, atherosclerosis. sclerosis, obesity or gout. 347. A method of treating a disease, disorder or condition which is a disease of the central nervous system, comprising administering to a subject in need of such treatment an effective amount of a compound, as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 348. Method, according to claim 347, characterized by the fact that the disease of the central nervous system is Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease. 349. A method of treating a disease, disorder or condition which is a lung disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 350. Method according to claim 349, characterized by the fact that the lung disease is asthma, COPD or idiopathic pulmonary fibrosis. 351. A method of treating a disease, disorder or condition which is liver disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 352. Method according to claim 351, characterized by the fact that the liver disease is NASH syndrome, viral hepatitis or cirrhosis. 353. A method of treating a disease, disorder or condition which is a pancreatic disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336 , or a pharmaceutical composition as defined in claim 337. 354. Method according to claim 353, characterized by the fact that the pancreatic disease is acute pancreatitis or chronic pancreatitis. 355. A method of treating a disease, disorder or condition which is kidney disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 356. Method, according to claim 355, characterized by the fact that the kidney disease is acute kidney injury or chronic kidney injury. 357. A method of treating a disease, disorder or condition which is an intestinal disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 358. Method according to claim 357, characterized by the fact that the intestinal disease is Crohn's disease or ulcerative colitis. 359. A method of treating a disease, disorder or condition which is a skin disease, comprising administering to an individual in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 360. Method according to claim 359, characterized by the fact that the skin disease is psoriasis. 361. A method of treating a disease, disorder or condition which is a musculoskeletal disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition, as defined in claim 337. 362. Method according to claim 361, characterized by the fact that the musculoskeletal disease is scleroderma. 363. A method of treating a disease, disorder or condition which is a vessel disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 364. Method according to claim 363, characterized by the fact that the vessel disease is giant cell arteritis. 365. A method of treating a disease, disorder or condition which is a bone disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 366. Method according to claim 365, characterized in that the bone disease is osteoarthritis, osteoporosis or osteopetrosis disorders. 367. A method of treating a disease, disorder or condition which is an eye disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 368. Method according to claim 367, characterized by the fact that the eye disease is glaucoma or macular degeneration. 369. A method of treating a disease, disorder or condition which is a disease caused by a viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound, as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 370. Method, according to claim 369, characterized by the fact that the diseases caused by viral infection are HIV or AIDS. 371. A method of treating a disease, disorder or condition that is an autoimmune disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 372. Method according to claim 371, characterized by the fact that the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroiditis, Addison's disease, pernicious anemia, cancer and aging. 373. Method for treating a disease, disorder or condition which is cancer or aging, characterized in that it comprises administering to an individual in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 374. Method, characterized by the fact that it is to treat a disease, disorder or condition that is a cancer selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying NLRP3 mutation or overexpression; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoid treatment; Langerhan cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML); chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis, which comprises administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 336, or a pharmaceutical composition as defined in claim 337. 375. Method according to claim 374, characterized by the fact that the cancer is MDS. 376. Method according to claim 374, characterized in that the cancer is non-small lung cancer. 377. Method according to claim 374, characterized by the fact that the cancer is acute lymphoblastic leukemia. 378. Method according to claim 374, characterized by the fact that the cancer is LCH. 379. Method according to claim 374, characterized by the fact that the cancer is multiple myeloma. 380. Method according to claim 374, characterized by the fact that the cancer is promyelocytic leukemia. 381. Method according to claim 374, characterized by the fact that the cancer is acute myeloid leukemia (AML). 382. Method according to claim 374, characterized by the fact that the cancer is chronic myeloid leukemia (CML). 383. Method according to claim 374, characterized by the fact that the cancer is gastric cancer. 384. Method according to claim 374, characterized by the fact that the cancer is lung cancer metastasis. 385. The method of any one of claims 338 to 384, further comprising administering a therapeutically effective amount of an anti-TNFα agent to the subject. 386. Method according to claim 385, characterized in that the NLRP3 antagonist is administered to the individual prior to the administration of the anti-TNFα agent to the individual. 387. Method according to claim 385, characterized in that the anti-TNFα agent is administered to the subject prior to the administration of the NLRP3 antagonist to the subject. 388. Method according to claim 385, characterized in that the NLRP3 antagonist and the anti-TNFα agent are administered to the subject at substantially the same time. 389. Method according to claim 385, characterized in that the NLRP3 antagonist and the anti-TNFα agent are formulated together in a single dosage form. 390. Compound, according to claim 1, characterized by the fact that [002665] m = 0, 1 or 2; [002666] n = 0, 1 or 2; [002667] o = 1 or 2; [002668] p = 0, 1, 2 or 3; wherein the sum of o and p is 1 to 4; [002669] where [002670] A is a pyrazolyl, [002671] B is pyridinyl. 391. A compound according to claim 390, characterized in that A is pyrazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 or 2 R2. 392. A compound according to claim 390, characterized in that A is pyrazolyl optionally substituted by 1 R1 and optionally substituted by 1 or 2 R2. 393. A compound according to claim 390, characterized in that A is pyrazolyl optionally substituted by 1 or 2 R1 and optionally substituted by 1 R2. 394. A compound according to any one of claims 390 to 393, characterized in that B is pyridin-4-yl. 395. Compound according to any one of claims- R7' R6' N R7' cations 390 to 394, characterized in that B is R6' . 396. Compound according to any one of the claims- (Y)q N cations 390 to 395, characterized in that B is R6 R7 ; R6 is selected from C1-C6 alkyl (eg methyl, ethyl or isopropyl) and C3-C10 cycloalkyl (eg cyclopropyl); R7 is selected from C1-C6 alkyl (for example methyl, ethyl or isopropyl), C1-C6 haloalkyl (for example trifluoromethyl) and C3-C10 cycloalkyl (for example cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted by one or more C1-C6 alkyl (eg methyl); q is 0, 1 or 2; each Y is independently selected from C1-C6 alkyl (eg, methyl); or when two Y's are attached to the same carbon, the two Y's are taken together with the carbon to which they are attached to form a cyclopropyl ring.